PI3K/AKT/mTOR Axis in Cancer: From Pathogenesis to Treatment

Abstract

The PI3K/AKT/mTOR signaling axis is a pivotal regulator of key cellular functions, including proliferation, metabolism, survival, and immune modulation. In cancer, its dysregulation drives malignant transformation, tumor progression, therapeutic resistance, and immune evasion. Despite numerous studies, an integrated understanding of this pathway's multifaceted role in tumor biology and treatment remains incomplete. This review comprehensively outlines the oncogenic mechanisms governed by the PI3K/AKT/mTOR pathway, including its regulation of epithelial–mesenchymal transition, autophagy, apoptosis, glycolysis, ferroptosis, and lipid metabolism. We emphasize the dual role of autophagy, its interplay with therapeutic resistance, and its contextual impact on cancer dynamics. Moreover, we explore the epigenetic regulation of this axis by noncoding RNAs (miRNAs, lncRNAs, circRNAs) and its influence on tumor hallmarks. The review also highlights the pathway's involvement in modulating responses to chemotherapy, radiotherapy, and immunotherapy, as well as its role in remodeling the tumor microenvironment. We critically evaluate emerging therapeutic strategies targeting the PI3K/AKT/mTOR axis, including small-molecule inhibitors, phytochemicals, and nanoparticle-based systems. By elucidating the integrated landscape of this pathway, our review highlights its value as a central therapeutic target and offers insights into precision oncology approaches aimed at overcoming drug resistance and enhancing treatment efficacy.

Keywords

cancer therapy / chemotherapy and immunotherapy / drug delivery / molecular pathway / PI3K/AKT/mTOR axis

References

[1] R. L. Siegel, T. B. Kratzer, A. N. Giaquinto, H. Sung, A. Jemal, “Cancer Statistics, 2025,” CA: A Cancer Journal for Clinicians 75, no. 1 (2025): 10-45.

[2] D. Chakravarty, D. B. Solit, “Clinical Cancer Genomic Profiling,” Nature Reviews Genetics 22, no. 8 (2021): 483-501.

[3] A. Balmain, J. Gray, B. Ponder, “The Genetics and Genomics of Cancer,” Nature Genetics 33, no. 3 (2003): 238-244.

[4] M. R. Stratton, P. J. Campbell, P. A. Futreal, “The Cancer Genome,” Nature 458, no. 7239 (2009): 719-724.

[5] M. Roerden, S. Spranger, “Cancer Immune Evasion, Immunoediting and Intratumour Heterogeneity,” Nature Reviews Immunology 25, no. 5 (2025): 353-369.

[6] C. A. Klein, “Cancer Progression and the Invisible Phase of Metastatic Colonization,” Nature Reviews Cancer 20, no. 11 (2020): 681-694.

[7] A. M. Pinzaru, S. F. Tavazoie, “Transfer RNAs as Dynamic and Critical Regulators of Cancer Progression,” Nature Reviews Cancer 23, no. 11 (2023): 746-761.

[8] L. Fabbri, A. Chakraborty, C. Robert, S. Vagner, “The Plasticity of mRNA Translation During Cancer Progression and Therapy Resistance,” Nature Reviews Cancer 21, no. 9 (2021): 558-577.

[9] R. Derynck, S. J. Turley, R. J. Akhurst, “TGFβ Biology in Cancer Progression and Immunotherapy,” Nature Reviews Clinical Oncology 18, no. 1 (2021): 9-34.

[10] S. Jaillon, A. Ponzetta, D. Di Mitri, A. Santoni, R. Bonecchi, A. Mantovani, “Neutrophil Diversity and Plasticity in Tumour Progression and Therapy,” Nature Reviews Cancer 20, no. 9 (2020): 485-503.

[11] E. C. Cheung, K. H. Vousden, “The Role of ROS in Tumour Development and Progression,” Nature Reviews Cancer 22, no. 5 (2022): 280-297.

[12] V. Makwana, S. Rudrawar, S. Anoopkumar-Dukie, “Signalling Transduction of O-GlcNAcylation and PI3K/AKT/mTOR-axis in Prostate Cancer,” Biochimica et Biophysica Acta - Molecular Basis of Disease 1867, no. 7 (2021): 166129.

[13] Y.-C. Su, W.-C. Lee, C.-C. Wang, S-An Yeh, W.-H. Chen, P.-J. Chen, “Targeting PI3K/AKT/mTOR Signaling Pathway as a Radiosensitization in Head and Neck Squamous Cell Carcinomas,” International Journal of Molecular Sciences 23, no. 24 (2022): 15749.

[14] P. J. Kaboli, S. Imani, M. Jomhori, K. H. Ling, “Chemoresistance in Breast Cancer: PI3K/Akt Pathway Inhibitors vs the Current Chemotherapy,” American Journal of Cancer Research 11, no. 10 (2021): 5155-5183.

[15] J. Jin, J. He, X. Li, X. Ni, X. Jin, “The Role of Ubiquitination and Deubiquitination in PI3K/AKT/mTOR Pathway: A Potential Target for Cancer Therapy,” Gene 889 (2023): 147807.

[16] B. Ul Islam, M. Suhail, M. S. Khan, et al., “Flavonoids and PI3K/Akt/mTOR Signaling Cascade: A Potential Crosstalk in Anticancer Treatment,” Current Medicinal Chemistry 28, no. 39 (2021): 8083-8097.

[17] S. Stanciu, F. Ionita-Radu, C. Stefani, et al., “Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects,” International Journal of Molecular Sciences 23, no. 17 (2022): 10132.

[18] N. Vasan, L. C. Cantley, “At a Crossroads: How to Translate the Roles of PI3K in Oncogenic and Metabolic Signalling Into Improvements in Cancer Therapy,” Nature Reviews Clinical Oncology 19, no. 7 (2022): 471-485.

[19] Y. Samuels, Z. Wang, A. Bardelli, et al., “High Frequency of Mutations of the PIK3CA Gene in human Cancers,” Science 304, no. 5670 (2004): 554.

[20] T. Utermark, T. Rao, H. Cheng, et al., “The p110α and p110β Isoforms of PI3K Play Divergent Roles in Mammary Gland Development and Tumorigenesis,” Genes & Development 26, no. 14 (2012): 1573-1586.

[21] S. K. Luk, R. P. Piekorz, B. Nürnberg, S.-S. Tony To, “The Catalytic Phosphoinositol 3-kinase Isoform p110δ Is Required for Glioma Cell Migration and Invasion,” European Journal of Cancer 48, no. 1 (2012): 149-157.

[22] A. C. Tan, “Targeting the PI3K/Akt/mTOR Pathway in Non-small Cell Lung Cancer (NSCLC),” Thoracic Cancer 11, no. 3 (2020): 511-518.

[23] L. C. Foukas, I. M. Berenjeno, A. Gray, A. Khwaja, B. Vanhaesebroeck, “Activity of any Class IA PI3K Isoform Can Sustain Cell Proliferation and Survival,” PNAS 107, no. 25 (2010): 11381-11386.

[24] D. Tewari, P. Patni, A. Bishayee, A. N. Sah, A. Bishayee, “Natural Products Targeting the PI3K-Akt-mTOR Signaling Pathway in Cancer: A Novel Therapeutic Strategy,” Seminars in Cancer Biology 80 (2022): 1-17.

[25] P. D. Leiphrakpam, C. Are, “PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment,” International Journal of Molecular Sciences 25, no. 6 (2024): 3178.

[26] F. E. Marquard, M. Jücker, “PI3K/AKT/mTOR Signaling as a Molecular Target in Head and Neck Cancer,” Biochemical Pharmacology 172 (2020): 113729.

[27] C. Xue, G. Li, J. Lu, L. Li, “Crosstalk Between circRNAs and the PI3K/AKT Signaling Pathway in Cancer Progression,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 400.

[28] S. J. Rodgers, C. A. Mitchell, L. M. Ooms, “The Mechanisms of Class 1A PI3K and Wnt/β-catenin Coupled Signaling in Breast Cancer,” Biochemical Society Transactions 51, no. 4 (2023): 1459-1472.

[29] H. Li, X. Wen, Y. Ren, et al., “Targeting PI3K family With Small-molecule Inhibitors in Cancer Therapy: Current Clinical Status and Future Directions,” Molecular Cancer 23, no. 1 (2024): 164.

[30] L. Yu, J. Wei, P. Liu, “Attacking the PI3K/Akt/mTOR Signaling Pathway for Targeted Therapeutic Treatment in human Cancer,” Seminars in Cancer Biology 85 (2022): 69-94.

[31] J. Liang, H. Li, J. Han, et al., “Mex3a interacts With LAMA2 to Promote Lung Adenocarcinoma Metastasis via PI3K/AKT Pathway,” Cell Death & Disease 11, no. 8 (2020): 614.

[32] H. Rehman, D. S. Chandrashekar, C. Balabhadrapatruni, et al., “ARID1A-deficient Bladder Cancer Is Dependent on PI3K Signaling and Sensitive to EZH2 and PI3K Inhibitors,” JCI Insight 7, no. 16 (2022): e155899.

[33] F. Su, R. Xiao, R. Chen, et al., “WIPF1 promotes Gastric Cancer Progression by Regulating PI3K/Akt Signaling in a Myocardin-dependent Manner,” Iscience 26, no. 11 (2023): 108273.

[34] W. L. Lv, Y. Y. Hu, Z. N. Li, W. Zhang, Q. Pan, “PAX3 silencing Suppresses Gastric Cancer Proliferation and Angiogenesis via MET/PI3K Signaling,” Neoplasma 67, no. 2 (2020): 304-311.

[35] A. Zhang, N. A. Lau, A. Wong, et al., “Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers,” Cancer Research Communications 3, no. 11 (2023): 2358-2374.

[36] X. Ren, M. Long, Z. Li, et al., “Oncogene PRR14 Promotes Breast Cancer Through Activation of PI3K Signal Pathway and Inhibition of CHEK2 Pathway,” Cell Death & Disease 11, no. 6 (2020): 464.

[37] Y. Wang, Y. Wang, W. Liu, et al., “TIM-4 Orchestrates Mitochondrial Homeostasis to Promote Lung Cancer Progression via ANXA2/PI3K/AKT/OPA1 Axis,” Cell Death & Disease 14, no. 2 (2023): 141.

[38] N. B. Collins, R. Al Abosy, B. C. Miller, et al., “PI3K Activation Allows Immune Evasion by Promoting an Inhibitory Myeloid Tumor Microenvironment,” Journal for ImmunoTherapy of Cancer 10, no. 3 (2022): e003402.

[39] C.-H. Chan, L.-W. Chiou, T.-Y. Lee, et al., “PAK and PI3K Pathway Activation Confers Resistance to KRAS(G12C) Inhibitor sotorasib,” British Journal of Cancer 128, no. 1 (2023): 148-159.

[40] H. Li, L. Prever, E. Hirsch, F. Gulluni, “Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer,” Cancers (Basel) 13, no. 14 (2021): 3517.

[41] A. Khatpe, A. Adebayo, C. Herodotou, B. Kumar, H. Nakshatri, “Nexus Between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer,” Cancers (Basel) 13, no. 3 (2021): 369.

[42] J. S. O'Donnell, D. Massi, M. W. L. Teng, M. Mandala, “PI3K-AKT-mTOR Inhibition in Cancer Immunotherapy, Redux,” Seminars in Cancer Biology 48 (2018): 91-103.

[43] G. Hoxhaj, B. D. Manning, “The PI3K-AKT Network at the Interface of Oncogenic Signalling and Cancer Metabolism,” Nature Reviews Cancer 20, no. 2 (2020): 74-88.

[44] B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, G. B. Mills, “Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery,” Nature Reviews Drug Discovery 4, no. 12 (2005): 988-1004.

[45] Y. He, M. M. Sun, G. G. Zhang, et al., “Targeting PI3K/Akt Signal Transduction for Cancer Therapy,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 425.

[46] B. Vanhaesebroeck, J. Guillermet-Guibert, M. Graupera, B. Bilanges, “The Emerging Mechanisms of Isoform-specific PI3K Signalling,” Nature Reviews Molecular Cell Biology 11, no. 5 (2010): 329-341.

[47] L. M. Thorpe, H. Yuzugullu, J. J. Zhao, “PI3K in Cancer: Divergent Roles of Isoforms, Modes of Activation and Therapeutic Targeting,” Nature Reviews Cancer 15, no. 1 (2015): 7-24.

[48] A. B. Hanker, V. Kaklamani, C. L. Arteaga, “Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors,” Cancer Discovery 9, no. 4 (2019): 482-491.

[49] D. A. Fruman, H. Chiu, B. D. Hopkins, S. Bagrodia, L. C. Cantley, R. T. Abraham, “The PI3K Pathway in Human Disease,” Cell 170, no. 4 (2017): 605-635.

[50] X. Ye, T. Brabletz, Y. Kang, et al., “Upholding a Role for EMT in Breast Cancer Metastasis,” Nature 547, no. 7661 (2017): E1-E3.

[51] T. Brabletz, R. Kalluri, M. A. Nieto, R. A. Weinberg, “EMT in Cancer,” Nature Reviews Cancer 18, no. 2 (2018): 128-134.

[52] N. M. Aiello, T. Brabletz, Y. Kang, M. A. Nieto, R. A. Weinberg, B. Z. Stanger, “Upholding a Role for EMT in Pancreatic Cancer Metastasis,” Nature 547, no. 7661 (2017): E7-E8.

[53] B. D. Craene, G. Berx, “Regulatory Networks Defining EMT During Cancer Initiation and Progression,” Nature Reviews Cancer 13, no. 2 (2013): 97-110.

[54] C. Li, G. Balazsi, “A Landscape View on the Interplay Between EMT and Cancer Metastasis,” NPJ Systems Biology and Applications 4, no. 1 (2018): 34.

[55] J. Van Staalduinen, D. Baker, P. Ten Dijke, H. Van Dam, “Epithelial-mesenchymal-transition-inducing Transcription Factors: New Targets for Tackling Chemoresistance in Cancer?,” Oncogene 37, no. 48 (2018): 6195-6211.

[56] C. Wang, Z. Yang, En Xu, et al., “Apolipoprotein C-II Induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway,” Clinical and Translational Medicine 11, no. 8 (2021): e522.

[57] H. Chen, L. Ma, W. Yang, Y. Li, Z. Ji, “POLR3G Promotes EMT via PI3K/AKT Signaling Pathway in Bladder Cancer,” Faseb Journal 37, no. 12 (2023): e23260.

[58] Q. Shao, Z. Zhang, R. Cao, H. Zang, W. Pei, T. Sun, “CPA4 Promotes EMT in Pancreatic Cancer via Stimulating PI3K-AKT-mTOR Signaling,” OncoTargets and Therapy 13 (2020): 8567-8580.

[59] F. Peng, Q. Xu, X. Jing, et al., “GPX2 promotes EMT and Metastasis in Non-small Cell Lung Cancer by Activating PI3K/AKT/mTOR/Snail Signaling Axis,” FASEB Bioadv 5, no. 6 (2023): 233-250.

[60] J. Hu, G. Li, Z. Liu, et al., “Bicarbonate Transporter SLC4A7 Promotes EMT and Metastasis of HNSCC by Activating the PI3K/AKT/mTOR Signaling Pathway,” Molecular Carcinogenesis 62, no. 5 (2023): 628-640.

[61] D. Rodriguez-Abreu, A. Bordoni, E. Zucca, “Epidemiology of Hematological Malignancies,” Annals of Oncology 18 (2007): i3-i8.

[62] R. R. Misra, P. F. Pinsky, S. Srivastava, “Prognostic Factors for Hematologic Cancers,” Hematology/oncology Clinics of North America 14, no. 4 (2000): 907-924.

[63] D. Li, et al., “PAK5 Induces EMT and Promotes Cell Migration and Invasion by Activating the PI3K/AKT Pathway in Ovarian Cancer,” Analytical Cellular Pathology (Amsterdam) 2018 (2018): 8073124.

[64] C. Sun, Y. Tao, Y. Gao, et al., “F-box Protein 11 Promotes the Growth and Metastasis of Gastric Cancer via PI3K/AKT Pathway-mediated EMT,” Biomedicine & Pharmacotherapy 98 (2018): 416-423.

[65] J. Yang, Z. Zeng, Y. Peng, J. Chen, L. Pan, D. Pan, “IL-7 Splicing Variant IL-7δ5 Induces EMT and Metastasis of human Breast Cancer Cell Lines MCF-7 and BT-20 Through Activation of PI3K/Akt Pathway,” Histochemistry and Cell Biology 142, no. 4 (2014): 401-410.

[66] W. Xu, Z. Yang, N. Lu, “A New Role for the PI3K/Akt Signaling Pathway in the Epithelial-mesenchymal Transition,” Cell Adhesion & Migration 9, no. 4 (2015): 317-324.

[67] G.-H. Ha, J.-S. Park, E.-K. Y. Breuer, “TACC3 promotes Epithelial-mesenchymal Transition (EMT) Through the Activation of PI3K/Akt and ERK Signaling Pathways,” Cancer Letters 332, no. 1 (2013): 63-73.

[68] Z. Ma, S. Lou, Z. Jiang, “PHLDA2 regulates EMT and Autophagy in Colorectal Cancer via the PI3K/AKT Signaling Pathway,” Aging (Albany NY) 12, no. 9 (2020): 7985-8000.

[69] R. Wei, Y. Xiao, Y. Song, H. Yuan, J. Luo, W. Xu, “FAT4 regulates the EMT and Autophagy in Colorectal Cancer Cells in Part via the PI3K-AKT Signaling Axis,” Journal of Experimental & Clinical Cancer Research 38, no. 1 (2019): 112.

[70] L. M. Feng, X. F. Wang, Q. X. Huang, “Thymoquinone Induces Cytotoxicity and Reprogramming of EMT in Gastric Cancer Cells by Targeting PI3K/Akt/mTOR Pathway,” Journal of Biosciences 42, no. 4 (2017): 547-554.

[71] J. Deng, X. Bai, X. Feng, et al., “Inhibition of PI3K/Akt/mTOR Signaling Pathway Alleviates Ovarian Cancer Chemoresistance Through Reversing Epithelial-mesenchymal Transition and Decreasing Cancer Stem Cell Marker Expression,” BMC Cancer 19, no. 1 (2019): 618.

[72] R. Mathew, V. Karantza-Wadsworth, E. White, “Role of Autophagy in Cancer,” Nature Reviews Cancer 7, no. 12 (2007): 961-967.

[73] J. M. M. Levy, C. G. Towers, A. Thorburn, “Targeting Autophagy in Cancer,” Nature Reviews Cancer 17, no. 9 (2017): 528-542.

[74] R. A. Nixon, “The Role of Autophagy in Neurodegenerative Disease,” Nature Medicine 19, no. 8 (2013): 983-997.

[75] F. M. Menzies, A. Fleming, D. C. Rubinsztein, “Compromised Autophagy and Neurodegenerative Diseases,” Nature Reviews Neuroscience 16, no. 6 (2015): 345-357.

[76] W. Martinet, M. W. M. Knaapen, M. M. Kockx, G. R. Y. De Meyer, “Autophagy in Cardiovascular Disease,” Trends in Molecular Medicine 13, no. 11 (2007): 482-491.

[77] J. M. Bravo-San Pedro, G. Kroemer, L. Galluzzi, “Autophagy and Mitophagy in Cardiovascular Disease,” Circulation Research 120, no. 11 (2017): 1812-1824.

[78] M. Kitada, D. Koya, “Autophagy in Metabolic Disease and Ageing,” Nature Reviews Endocrinology 17, no. 11 (2021): 647-661.

[79] F. Wang, J. Jia, B. Rodrigues, “Autophagy, Metabolic Disease, and Pathogenesis of Heart Dysfunction,” Canadian Journal of Cardiology 33, no. 7 (2017): 850-859.

[80] V. Deretic, T. Saitoh, S. Akira, “Autophagy in Infection, Inflammation and Immunity,” Nature Reviews Immunology 13, no. 10 (2013): 722-737.

[81] Z. Xu, Xu Han, D. Ou, et al., “Targeting PI3K/AKT/mTOR-mediated Autophagy for Tumor Therapy,” Applied Microbiology and Biotechnology 104, no. 2 (2020): 575-587.

[82] H. Dai, W. Hu, L. Zhang, et al., “FGF21 facilitates Autophagy in Prostate Cancer Cells by Inhibiting the PI3K-Akt-mTOR Signaling Pathway,” Cell Death & Disease 12, no. 4 (2021): 303.

[83] M. Zhang, J. Wang, Y. Guo, H. Yue, L. Zhang, “Activation of PI3K/AKT/mTOR Signaling Axis by UBE2S Inhibits Autophagy Leading to Cisplatin Resistance in Ovarian Cancer,” Journal of Ovarian Research 16, no. 1 (2023): 240.

[84] H. Li, S. Zhao, L. Shen, et al., “E2F2 inhibition Induces Autophagy via the PI3K/Akt/mTOR Pathway in Gastric Cancer,” Aging (Albany NY) 13, no. 10 (2021): 13626-13643.

[85] J. Ren, Z. Hu, G. Niu, et al., “Annexin A1 Induces Oxaliplatin Resistance of Gastric Cancer Through Autophagy by Targeting PI3K/AKT/mTOR,” Faseb Journal 37, no. 3 (2023): e22790.

[86] R. Lu, Z. Yang, G. Xu, S. Yu, “miR-338 Modulates Proliferation and Autophagy by PI3K/AKT/mTOR Signaling Pathway in Cervical Cancer,” Biomedicine & Pharmacotherapy 105 (2018): 633-644.

[87] C. Li, X. Hou, S. Yuan, et al., “High Expression of TREM2 Promotes EMT via the PI3K/AKT Pathway in Gastric Cancer: Bioinformatics Analysis and Experimental Verification,” Journal of Cancer 12, no. 11 (2021): 3277-3290.

[88] B. Wang, L. Wang, Y. Lu, et al., “GRSF1 promotes Tumorigenesis and EMT-mediated Metastasis Through PI3K/AKT Pathway in Gastric Cancer,” Biochemical and Biophysical Research Communications 555 (2021): 61-66.

[89] J. Wei, Z. Zheng, X. Hou, et al., “Echinacoside Inhibits Colorectal Cancer Metastasis via Modulating the Gut Microbiota and Suppressing the PI3K/AKT Signaling Pathway,” Journal of Ethnopharmacology 318, no. Pt A (2024): 116866.

[90] H. Xu, J. Wang, M. Al-Nusaif, H. Ma, W. Le, “CCL2 promotes Metastasis and Epithelial-mesenchymal Transition of Non-small Cell Lung Cancer via PI3K/Akt/mTOR and Autophagy Pathways,” Cell Proliferation 57, no. 3 (2024): e13560.

[91] S. Liang, H. Guo, K. Ma, et al., “A PLCB1-PI3K-AKT Signaling Axis Activates EMT to Promote Cholangiocarcinoma Progression,” Cancer Research 81, no. 23 (2021): 5889-5903.

[92] X. Lu, F. Yang, D. Chen, et al., “Quercetin Reverses Docetaxel Resistance in Prostate Cancer via Androgen Receptor and PI3K/Akt Signaling Pathways,” International Journal of Biological Sciences 16, no. 7 (2020): 1121-1134.

[93] J.-C. Xu, T.-Y. Chen, L.-T. Liao, et al., “NETO2 promotes Esophageal Cancer Progression by Inducing Proliferation and Metastasis via PI3K/AKT and ERK Pathway,” International Journal of Biological Sciences 17, no. 1 (2021): 259-270.

[94] M. Chi, J. Liu, C. Mei, et al., “TEAD4 functions as a Prognostic Biomarker and Triggers EMT via PI3K/AKT Pathway in Bladder Cancer,” Journal of Experimental & Clinical Cancer Research 41, no. 1 (2022): 175.

[95] J. Xu, S. Liu, X. Yang, S. Cao, Y. Zhou, “Paracrine HGF Promotes EMT and Mediates the Effects of PSC on Chemoresistance by Activating c-Met/PI3K/Akt Signaling in Pancreatic Cancer in Vitro,” Life Sciences 263 (2020): 118523.

[96] Xu Chen, W. Wang, Y. Li, et al., “MYSM1 inhibits human Colorectal Cancer Tumorigenesis by Activating miR-200 family Members/CDH1 and Blocking PI3K/AKT Signaling,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 341.

[97] F. Gao, S. Liu, J. Wang, et al., “TSP50 facilitates Breast Cancer Stem Cell-Like Properties Maintenance and Epithelial-mesenchymal Transition via PI3K p110α Mediated Activation of AKT Signaling Pathway,” Journal of Experimental & Clinical Cancer Research 43, no. 1 (2024): 201.

[98] L. Chen, J. Qing, Y. Xiao, X. Huang, Y. Chi, Z. Chen, “TIM-1 Promotes Proliferation and Metastasis, and Inhibits Apoptosis, in Cervical Cancer Through the PI3K/AKT/p53 Pathway,” BMC Cancer 22, no. 1 (2022): 370.

[99] Y. Chen, S. Chen, K. Chen, L. Ji, S. Cui, “Magnolol and 5-fluorouracil Synergy Inhibition of Metastasis of Cervical Cancer Cells by Targeting PI3K/AKT/mTOR and EMT Pathways,” Chinese Herbal Medicines 16, no. 1 (2024): 94-105.

[100] L. Chen, Q. Wu, X. Xu, et al., “Cancer/Testis Antigen LDHC Promotes Proliferation and Metastasis by Activating the PI3K/Akt/GSK-3β-signaling Pathway and the in Lung Adenocarcinoma,” Experimental Cell Research 398, no. 2 (2021): 112414.

[101] M.-G. F. Guefack, D. Talukdar, R. Mukherjee, et al., “Hypericum Roeperianum Bark Extract Suppresses Breast Cancer Proliferation via Induction of Apoptosis, Downregulation of PI3K/Akt/mTOR Signaling Cascade and Reversal of EMT,” Journal of Ethnopharmacology 319, no. Pt 1 (2024): 117093.

[102] Y. Li, Y. Li, J. Luo, et al., “FAM126A interacted With ENO1 Mediates Proliferation and Metastasis in Pancreatic Cancer via PI3K/AKT Signaling Pathway,” Cell Death Discovery 8, no. 1 (2022): 248.

[103] J.-X. Gu, Ke Huang, W.-L. Zhao, et al., “NCAPD2 augments the Tumorigenesis and Progression of human Liver Cancer via the PI3K‑Akt‑mTOR Signaling Pathway,” International Journal of Molecular Medicine 54, no. 4 (2024): 84.

[104] X.-P. Tan, Y. He, Y.-N. Huang, et al., “Lomerizine 2HCl Inhibits Cell Proliferation and Induces Protective Autophagy in Colorectal Cancer via the PI3K/Akt/mTOR Signaling Pathway,” MedComm 2, no. 3 (2021): 453-466.

[105] Y. Liu, H. Li, Z. Zheng, et al., “Rosa Rugosa Polysaccharide Induces Autophagy-mediated Apoptosis in human Cervical Cancer Cells via the PI3K/AKT/mTOR Pathway,” International Journal of Biological Macromolecules 212 (2022): 257-274.

[106] H. Dai, W. Hu, L. Zhang, et al., “FGF21 facilitates Autophagy in Prostate Cancer Cells by Inhibiting the PI3K-Akt-mTOR Signaling Pathway,” Cell Death & Disease 12, no. 4 (2021): 303.

[107] A.-J. Jhou, H.-C. Chang, C.-C. Hung, et al., “Chlorpromazine, an Antipsychotic Agent, Induces G2/M Phase Arrest and Apoptosis via Regulation of the PI3K/AKT/mTOR-mediated Autophagy Pathways in human Oral Cancer,” Biochemical Pharmacology 184 (2021): 114403.

[108] X. Fan, Y. He, G. Wu, et al., “Sirt3 activates Autophagy to Prevent DOX-induced Senescence by Inactivating PI3K/AKT/mTOR Pathway in A549 Cells,” Biochimica Et Biophysica Acta (BBA)—Molecular Cell Research 1870, no. 2 (2023): 119411.

[109] L. Deng, X. Wu, X. Zhu, et al., “Combination Effect of Curcumin With Docetaxel on the PI3K/AKT/mTOR Pathway to Induce Autophagy and Apoptosis in Esophageal Squamous Cell Carcinoma,” American Journal of Translational Research 13, no. 1 (2021): 57-72.

[110] J.-L. Pang, L.-S. Xu, Q. Zhao, et al., “Sodium Cantharidate Promotes Autophagy in Breast Cancer Cells by Inhibiting the PI3K-Akt-mTOR Signaling Pathway,” Frontiers in Pharmacology 13 (2022): 1000377.

[111] K. Sundarraj, A. Raghunath, L. Panneerselvam, E. Perumal, “Fisetin Inhibits Autophagy in HepG2 Cells via PI3K/Akt/mTOR and AMPK Pathway,” Nutrition and Cancer 73, no. 11-12 (2021): 2502-2514.

[112] J. Yang, C. Pi, G. Wang, “Inhibition of PI3K/Akt/mTOR Pathway by Apigenin Induces Apoptosis and Autophagy in Hepatocellular Carcinoma Cells,” Biomedicine & Pharmacotherapy 103 (2018): 699-707.

[113] Li Rong, Z. Li, X. Leng, et al., “Salidroside Induces Apoptosis and Protective Autophagy in human Gastric Cancer AGS Cells Through the PI3K/Akt/mTOR Pathway,” Biomedicine & Pharmacotherapy 122 (2020): 109726.

[114] K. Wang, J. Tang, S. Fan, et al., “ABBV-744 Induces Autophagy in Gastric Cancer Cells by Regulating PI3K/AKT/mTOR/p70S6k and MAPK Signaling Pathways,” Neoplasia 45 (2023): 100936.

[115] H. Bi, X. Hou, Q. Shen, et al., “Knockdown of KIF15 Suppresses Proliferation of Prostate Cancer Cells and Induces Apoptosis Through PI3K/Akt Signaling Pathway,” Cell Death Discovery 9, no. 1 (2023): 326.

[116] Y. Zhang, Q. Huang, Q. Xu, C. Jia, Y. Xia, “Pimavanserin Tartrate Induces Apoptosis and Cytoprotective Autophagy and Synergizes With Chemotherapy on Triple Negative Breast Cancer,” Biomedicine & Pharmacotherapy 168 (2023): 115665.

[117] X. Gao, Y. Jiang, Qi Xu, et al., “4-Hydroxyderricin Promotes Apoptosis and Cell Cycle Arrest Through Regulating PI3K/AKT/mTOR Pathway in Hepatocellular Cells,” Foods 10, no. 9 (2021): 2036.

[118] M.-L. Zhu, P.-M. Zhang, M. Jiang, S.-W. Yu, Lu Wang, “Myricetin Induces Apoptosis and Autophagy by Inhibiting PI3K/Akt/mTOR Signalling in human Colon Cancer Cells,” BMC Complementary Medicine and Therapies 20, no. 1 (2020): 209.

[119] E-Ji Han, E.-Y. Choi, S.-J. Jeon, et al., “Piperlongumine Induces Apoptosis and Autophagy via the PI3K/Akt/mTOR Pathway in KB human Cervical Cancer Cells,” Food and Chemical Toxicology 180 (2023): 114051.

[120] P. He, Y. He, J. Ma, et al., “Thymoquinone Induces Apoptosis and Protective Autophagy in Gastric Cancer Cells by Inhibiting the PI3K/Akt/mTOR Pathway,” Phytotherapy Research 37, no. 8 (2023): 3467-3480.

[121] M. L. Abdullah, O. Al-Shabanah, Z. K. Hassan, M. M. Hafez, “Eugenol-Induced Autophagy and Apoptosis in Breast Cancer Cells via PI3K/AKT/FOXO3a Pathway Inhibition,” International Journal of Molecular Sciences 22, no. 17 (2021): 9243.

[122] X. Chen, R. Kang, G. Kroemer, D. Tang, “Broadening Horizons: The Role of Ferroptosis in Cancer,” Nature Reviews Clinical Oncology 18, no. 5 (2021): 280-296.

[123] G. Lei, L. Zhuang, B. Gan, “Targeting Ferroptosis as a Vulnerability in Cancer,” Nature Reviews Cancer 22, no. 7 (2022): 381-396.

[124] J. P. Friedmann Angeli, D. V. Krysko, M. Conrad, “Ferroptosis at the Crossroads of Cancer-acquired Drug Resistance and Immune Evasion,” Nature Reviews Cancer 19, no. 7 (2019): 405-414.

[125] X. Jiang, B. R. Stockwell, M. Conrad, “Ferroptosis: Mechanisms, Biology and Role in Disease,” Nature Reviews Molecular Cell Biology 22, no. 4 (2021): 266-282.

[126] J. Li, JiL Jiang, YiM Chen, WQi Lu, “KLF2 inhibits Colorectal Cancer Progression and Metastasis by Inducing Ferroptosis via the PI3K/AKT Signaling Pathway,” Journal of Pathology and Clinical Research 9, no. 5 (2023): 423-435.

[127] L. Wang, J. Wang, L. Chen, “TIMP1 represses Sorafenib-triggered Ferroptosis in Colorectal Cancer Cells by Activating the PI3K/Akt Signaling Pathway,” Immunopharmacology and Immunotoxicology 45, no. 4 (2023): 419-425.

[128] J. Yi, J. Zhu, J. Wu, C. B. Thompson, X. Jiang, “Oncogenic Activation of PI3K-AKT-mTOR Signaling Suppresses Ferroptosis via SREBP-mediated Lipogenesis,” PNAS 117, no. 49 (2020): 31189-31197.

[129] Y. Jiang, J. Cui, M. Cui, R. Jing, “SLC7A11 promotes the Progression of Gastric Cancer and Regulates Ferroptosis Through PI3K/AKT Pathway,” Pathology, Research and Practice 248 (2023): 154646.

[130] M. Chen, A. H. Tan, J. Li, “Curcumin Represses Colorectal Cancer Cell Proliferation by Triggering Ferroptosis via PI3K/Akt/mTOR Signaling,” Nutrition and Cancer 75, no. 2 (2023): 726-733.

[131] W. Guo, Z. Wu, J. Chen, et al., “Nanoparticle Delivery of miR-21-3p Sensitizes Melanoma to anti-PD-1 Immunotherapy by Promoting Ferroptosis,” Journal for ImmunoTherapy of Cancer 10, no. 6 (2022): e004381.

[132] H. Wang, C. Qiao, Q. Guan, M. Wei, Z. Li, “Nanoparticle-mediated Synergistic Anticancer Effect of Ferroptosis and Photodynamic Therapy: Novel Insights and Perspectives,” Asian Journal of Pharmaceutical Sciences 18, no. 4 (2023): 100829.

[133] O. Warburg, “On respiratory Impairment in Cancer Cells,” Science 124, no. 3215 (1956): 269-270.

[134] S. Wang, Z. Cheng, Y. Cui, et al., “PTPRH Promotes the Progression of Non-small Cell Lung Cancer via Glycolysis Mediated by the PI3K/AKT/mTOR Signaling Pathway,” Journal of Translational Medicine 21, no. 1 (2023): 819.

[135] J. Cao, R. Cao, Y. Liu, T. Dai, “CPNE1 mediates Glycolysis and Metastasis of Breast Cancer Through Activation of PI3K/AKT/HIF-1α Signaling,” Pathology, Research and Practice 248 (2023): 154634.

[136] L. Chen, D. Zhuo, H. Yuan, “Circ_100395 impedes Malignancy and Glycolysis in Papillary Thyroid Cancer: Involvement of PI3K/AKT/mTOR Signaling Pathway,” Immunology Letters 246 (2022): 10-17.

[137] Qi Wang, B. Wang, W. Zhang, et al., “APLN Promotes the Proliferation, Migration, and Glycolysis of Cervical Cancer Through the PI3K/AKT/mTOR Pathway,” Archives of Biochemistry and Biophysics 755 (2024): 109983.

[138] Y. Zhang, Y. Wu, X. Su, “PLOD1 promotes Cell Growth and Aerobic Glycolysis by Regulating the SOX9/PI3K/Akt/mTOR Signaling Pathway in Gastric Cancer,” Frontiers in Bioscience (Landmark Ed) 26, no. 8 (2021): 322-334.

[139] J. Zhou, H. Sun, H. Zhou, Y. Liu, “SPAG4 enhances Mitochondrial Respiration and Aerobic Glycolysis in Colorectal Cancer Cells by Activating the PI3K/Akt Signaling Pathway,” Journal of Biochemical and Molecular Toxicology 38, no. 11 (2024): e70009.

[140] Z. Li, J. Liu, L. Que, X. Tang, “The Immunoregulatory Protein B7-H3 Promotes Aerobic Glycolysis in Oral Squamous Carcinoma via PI3K/Akt/mTOR Pathway,” Journal of Cancer 10, no. 23 (2019): 5770-5784.

[141] F. Li, Z. Zhang, P. Wang, et al., “ALC1 knockdown Enhances Cisplatin Cytotoxicity of Esophageal Squamous Cell Carcinoma Cells by Inhibition of Glycolysis Through PI3K/Akt Pathway,” Life Sciences 232 (2019): 116679.

[142] W. Zhu, Y. Li, D. Zhao, et al., “Dihydroartemisinin Suppresses Glycolysis of LNCaP Cells by Inhibiting PI3K/AKT Pathway and Downregulating HIF-1α Expression,” Life Sciences 233 (2019): 116730.

[143] X. Luo, C. Cheng, Z. Tan, et al., “Emerging Roles of Lipid Metabolism in Cancer Metastasis,” Molecular Cancer 16, no. 1 (2017): 76.

[144] G. Liu, B-Ye Sun, J. Sun, et al., “BRG1 regulates Lipid Metabolism in Hepatocellular Carcinoma Through the PIK3AP1/PI3K/AKT Pathway by Mediating GLMP Expression,” Digestive and Liver Disease 54, no. 5 (2022): 692-700.

[145] S. J. H. Ricoult, J. L. Yecies, I. Ben-Sahra, B. D. Manning, “Oncogenic PI3K and K-Ras Stimulate De Novo Lipid Synthesis Through mTORC1 and SREBP,” Oncogene 35, no. 10 (2016): 1250-1260.

[146] S. Zhao, L. Cheng, Y. Shi, J. Li, Q. Yun, H. Yang, “MIEF2 reprograms Lipid Metabolism to Drive Progression of Ovarian Cancer Through ROS/AKT/mTOR Signaling Pathway,” Cell Death & Disease 12, no. 1 (2021): 18.

[147] J. Zhao, X. Zhang, T. Gao, et al., “SIK2 enhances Synthesis of Fatty Acid and Cholesterol in Ovarian Cancer Cells and Tumor Growth Through PI3K/Akt Signaling Pathway,” Cell Death & Disease 11, no. 1 (2020): 25.

[148] Y. Gui, L. Wang, Z. Huang, “MiR-137 Inhibits Cervical Cancer Progression via Down-modulating Notch1 and Inhibiting the PI3K/AKT/mTOR Signaling Pathway,” Translational Cancer Research 10, no. 8 (2021): 3748-3756.

[149] X.-J. Gu, Y.-J. Li, F. Wang, T. Ye, “MiR-30e-3p Inhibits Gastric Cancer Development by Negatively Regulating THO Complex 2 and PI3K/AKT/mTOR Signaling,” World Journal of Gastrointestinal Oncology 14, no. 11 (2022): 2170-2182.

[150] B. Yang, Y. Wu, Y. Chen, et al., “MiR-5195-3p Targets the PCBP2/PI3K/AKT Pathway to Inhibit Melanoma Cell Proliferation and Migration,” Heliyon 9, no. 9 (2023): e19227.

[151] F. Zhang, K. Li, M. Pan, et al., “miR-589 Promotes Gastric Cancer Aggressiveness by a LIFR-PI3K/AKT-c-Jun Regulatory Feedback Loop,” Journal of Experimental & Clinical Cancer Research 37, no. 1 (2018): 152.

[152] Y. Liu, H. Yang, “MiR-18a-5p Attenuates HER2-positive Breast Cancer Development by Regulating PI3K/AKT Pathway,” Cancer Biology & Therapy 24, no. 1 (2023): 2224512.

[153] Ke Fu, L. Zhang, R. Liu, Qi Shi, X. Li, M. Wang, “MiR-125 Inhibited Cervical Cancer Progression by Regulating VEGF and PI3K/AKT Signaling Pathway,” World Journal of Surgical Oncology 18, no. 1 (2020): 115.

[154] H. Zhang, L. Li, C. Yuan, C. Wang, T. Gao, Z. Zheng, “MiR-489 Inhibited the Development of Gastric Cancer via Regulating HDAC7 and PI3K/AKT Pathway,” World Journal of Surgical Oncology 18, no. 1 (2020): 73.

[155] S. Liu, Q. Chen, Y. Wang, “MiR-125b-5p Suppresses the Bladder Cancer Progression via Targeting HK2 and Suppressing PI3K/AKT Pathway,” Human Cell 33, no. 1 (2020): 185-194.

[156] W.-D. Lu, Y. Zuo, Z. Xu, M. Zhang, “MiR-19a Promotes Epithelial-mesenchymal Transition Through PI3K/AKT Pathway in Gastric Cancer,” World Journal of Gastroenterology 21, no. 15 (2015): 4564-4573.

[157] H. Wu, J. Liu, Y. Zhang, Q. Li, Q. Wang, Z. Gu, “miR-22 Suppresses Cell Viability and EMT of Ovarian Cancer Cells via NLRP3 and Inhibits PI3K/AKT Signaling Pathway,” Clinical & Translational Oncology 23, no. 2 (2021): 257-264.

[158] J. Li, Z. Zhang, J. Hu, et al., “MiR-1246 Regulates the PI3K/AKT Signaling Pathway by Targeting PIK3AP1 and Inhibits Thyroid Cancer Cell Proliferation and Tumor Growth,” Molecular and Cellular Biochemistry 477, no. 3 (2022): 649-661.

[159] C. Li, G. Liang, S. Yang, et al., “LncRNA-LOC101928316 Contributes to Gastric Cancer Progression Through Regulating PI3K-Akt-mTOR Signaling Pathway,” Cancer Medicine 8, no. 9 (2019): 4428-4440.

[160] J. Zhou, S. Zhang, M. Luo, “LncRNA PCAT7 Promotes the Malignant Progression of Breast Cancer by Regulating ErbB/PI3K/Akt Pathway,” Future Oncology 17, no. 6 (2021): 701-710.

[161] M. Xia, W. Zhu, C. Tao, Y. Lu, F. Gao, “LncRNA LASTR Promote Lung Cancer Progression Through the miR-137/TGFA/PI3K/AKT Axis Through Integration Analysis,” Journal of Cancer 13, no. 4 (2022): 1086-1096.

[162] Bo Hao, H. Wen, Y. Sun, et al., “LncRNA-CASC7 Inhibits the Proliferation and Migration of Colon Cancer by Negatively Regulating the PI3K/Akt Signaling Pathway,” Journal of Gastrointestinal Oncology 12, no. 6 (2021): 2803-2813.

[163] W. Jiang, J. Kai, D. Li, Z. Wei, Y. Wang, W. Wang, “lncRNA HOXB-AS3 Exacerbates Proliferation, Migration, and Invasion of Lung Cancer via Activating the PI3K-AKT Pathway,” Journal of Cellular Physiology 235, no. 10 (2020): 7194-7203.

[164] X. Ma, H. Ren, Y. Zhang, B. Wang, H. Ma, “LncRNA RHPN1-AS1 Inhibition Induces Autophagy and Apoptosis in Prostate Cancer Cells via the miR-7-5p/EGFR/PI3K/AKT/mTOR Signaling Pathway,” Environmental Toxicology 37, no. 12 (2022): 3013-3027.

[165] G. Yang, Z. Li, L. Dong, F. Zhou, “lncRNA ADAMTS9-AS1 Promotes Bladder Cancer Cell Invasion, Migration, and Inhibits Apoptosis and Autophagy Through PI3K/AKT/mTOR Signaling Pathway,” International Journal of Biochemistry & Cell Biology 140 (2021): 106069.

[166] F. Zhou, J. Wang, X. Chi, X. Zhou, Z. Wang, “lncRNA TM4SF1-AS1 Activates the PI3K/AKT Signaling Pathway and Promotes the Migration and Invasion of Lung Cancer Cells,” Cancer Management and Research 12 (2020): 5527-5536.

[167] J. Hu, M. Wang, Y. Yang, Y. Xing, S. Li, “LncRNA DLEU2 Silencing Impedes the Migration, Invasion and EMT in Gastric Cancer Cell by Suppressing PI3K/AKT Signaling Pathway,” Immunopharmacology and Immunotoxicology 44, no. 5 (2022): 719-731.

[168] B. Yang, L. Li, Ge Tong, et al., “Circular RNA circ_001422 Promotes the Progression and Metastasis of Osteosarcoma via the miR-195-5p/FGF2/PI3K/Akt Axis,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 235.

[169] G.-C. Luo, L. Chen, J. Fang, Z.-J. Yan, “Hsa_circ_0030586 promotes Epithelial-mesenchymal Transition in Prostate Cancer via PI3K-AKT Signaling,” Bioengineered 12, no. 2 (2021): 11089-11107.

[170] Di Wu, H. Jia, Z. Zhang, S. Li, “Circ-PRMT5 Promotes Breast Cancer by the miR-509-3p/TCF7L2 Axis Activating the PI3K/AKT Pathway,” The Journal of Gene Medicine 23, no. 2 (2021): e3300.

[171] D. Wu, Y. Li, A. Xu, W. Tang, Bo Yu, “CircRNA RNA hsa_circ_0008234 Promotes Colon Cancer Progression by Regulating the miR-338-3p/ETS1 Axis and PI3K/AKT/mTOR Signaling,” Cancers (Basel) 15, no. 7 (2023): 2068.

[172] X. Lv, P. Li, J. Wang, et al., “hsa_circ_0000520 influences Herceptin Resistance in Gastric Cancer Cells Through PI3K-Akt Signaling Pathway,” Journal of Clinical Laboratory Analysis 34, no. 10 (2020): e23449.

[173] J. H. Xu, Y. Wang, D. Xu, “Hsa_circ_001569 is an Unfavorable Prognostic Factor and Promotes Cell Proliferation and Metastasis by Modulating PI3K-AKT Pathway in Breast Cancer,” Cancer Biomark 25, no. 2 (2019): 193-201.

[174] J. Liu, Q. Yu, X. Yang, “Circ_0102231 inactivates the PI3K/AKT Signaling Pathway by Regulating the miR-635/NOVA2 Pathway to Promote the Progression of Non-small Cell Lung Cancer,” Thorac Cancer 14, no. 35 (2023): 3453-3464.

[175] J. Si, J. Jin, J. Sai, et al., “Circular RNA Circ-PLCD1 Functions as a Tumor Suppressor in Non-small Cell Lung Cancer by Inactivation of PI3K/AKT Signaling Pathway,” Human Cell 35, no. 3 (2022): 924-935.

[176] K. Fang, S. Liang, D. Liu, Q. Yi, Y. Li, R. Zhu, “Hsa_circ_0003596 enhances the Development of Cell Renal Clear Cell Carcinoma Through the miR-502-5p/IGF1/PI3K/AKT Axis,” The Journal of Gene Medicine 25, no. 12 (2023): e3562.

[177] C. Yang, S. Zhang, L. Liu, et al., “Hsa_circ_0002496 promotes the Growth, Angiogenesis, and Stemness of Breast Cancer Cells via miR-433-3p/YWHAZ Cascade,” Thorac Cancer 14, no. 18 (2023): 1732-1741.

[178] J. Wang, J. Luo, G. Liu, X. Li, “Circular RNA hsa_circ_0008285 Inhibits Colorectal Cancer Cell Proliferation and Migration via the miR-382-5p/PTEN Axis,” Biochemical and Biophysical Research Communications 527, no. 2 (2020): 503-510.

[179] J. He, H. Fu, C. Li, Z. Deng, H. Chang, “Eriodictyol Inhibits Breast Carcinogenesis by Targeting circ_0007503 and Repressing PI3K/Akt Pathway,” Phytomedicine 102 (2022): 154159.

[180] F. L. Tu, X. Q. Guo, H. X. Wu, et al., “Circ-0001313/miRNA-510-5p/AKT2 Axis Promotes the Development and Progression of Colon Cancer,” American Journal of Translational Research 12, no. 1 (2020): 281-291.

[181] C. Zhang, J. Hu, Z. Liu, et al., “Hsa_circ_0000520 suppresses Vasculogenic Mimicry Formation and Metastasis in Bladder Cancer Through Lin28a/PTEN/PI3K Signaling,” Cellular & Molecular Biology Letters 29, no. 1 (2024): 118.

[182] He Wang, Q. Zhang, W. Cui, W. Li, J. Zhang, “Circ_0004018 suppresses Cell Proliferation and Migration in Hepatocellular Carcinoma via miR-1197/PTEN/PI3K/AKT Signaling Pathway,” Cell Cycle 20, no. 20 (2021): 2125-2136.

[183] X. Y. Zhang, L. Mao, “Circular RNA Circ_0000442 Acts as a Sponge of MiR-148b-3p to Suppress Breast Cancer via PTEN/PI3K/Akt Signaling Pathway,” Gene 766 (2021): 145113.

[184] J. Li, H. Qiu, Q. Dong, et al., “Androgen-targeted hsa_circ_0085121 Encodes a Novel Protein and Improves the Development of Prostate Cancer Through Facilitating the Activity of PI3K/Akt/mTOR Pathway and Enhancing AR-V7 Alternative Splicing,” Cell Death & Disease 15, no. 11 (2024): 848.

[185] Y.-F. Tang, Z.-H. Liu, L-Yi Zhang, et al., “circ_PPAPDC1A promotes Osimertinib Resistance by Sponging the miR-30a-3p/IGF1R Pathway in Non-small Cell Lung Cancer (NSCLC),” Molecular Cancer 23, no. 1 (2024): 91.

[186] X. Wang, R. Li, L. Feng, et al., “Hsa_circ_0001666 promotes Non-small Cell Lung Cancer Migration and Invasion Through miR-1184/miR-548I/AGO1 Axis,” Molecular Therapy Oncolytics 24 (2022): 597-611.

[187] L. Li, D. Liu, T. Chen, et al., “Hypoxia-enhanced YAP1-EIF4A3 Interaction Drives circ_0007386 Circularization by Competing With CRIM1 Pre-mRNA Linear Splicing and Promotes Non-small Cell Lung Cancer Progression,” Journal of Experimental & Clinical Cancer Research 43, no. 1 (2024): 200.

[188] C. Ju, M. Zhou, D. Du, et al., “EIF4A3-mediated circ_0042881 Activates the RAS Pathway via miR-217/SOS1 Axis to Facilitate Breast Cancer Progression,” Cell Death & Disease 14, no. 8 (2023): 559.

[189] H.-T. Liu, R.-R. Ma, B.-B. Lv, et al., “LncRNA-HNF1A-AS1 Functions as a Competing Endogenous RNA to Activate PI3K/AKT Signalling Pathway by Sponging miR-30b-3p in Gastric Cancer,” British Journal of Cancer 122, no. 12 (2020): 1825-1836.

[190] Y. Tian, Z.-H. Chen, P. Wu, et al., “MIR497HG-Derived miR-195 and miR-497 Mediate Tamoxifen Resistance via PI3K/AKT Signaling in Breast Cancer,” Advanced Science (Weinheim) 10, no. 12 (2023): e2204819.

[191] J. Hua, X. Wang, L. Ma, et al., “CircVAPA Promotes Small Cell Lung Cancer Progression by Modulating the miR-377-3p and miR-494-3p/IGF1R/AKT Axis,” Molecular Cancer 21, no. 1 (2022): 123.

[192] C. Mi, D. Zhang, Y. Li, et al., “miR-4677-3p Participates Proliferation and Metastases of Gastric Cancer Cell via CEMIP-PI3K/AKT Signaling Pathway,” Cell Cycle 20, no. 19 (2021): 1978-1987.

[193] L. Wang, Z. Zhang, X. Yu, et al., “SOX9/miR-203a Axis Drives PI3K/AKT Signaling to Promote Esophageal Cancer Progression,” Cancer Letters 468 (2020): 14-26.

[194] Q. Dai, T. Zhang, J. Pan, C. Li, “LncRNA UCA1 Promotes Cisplatin Resistance in Gastric Cancer via Recruiting EZH2 and Activating PI3K/AKT Pathway,” Journal of Cancer 11, no. 13 (2020): 3882-3892.

[195] F. Wang, Y. Luo, Le Zhang, M. Younis, L. Yuan, “The LncRNA RP11-301G19.1/miR-582-5p/HMGB2 Axis Modulates the Proliferation and Apoptosis of Multiple Myeloma Cancer Cells via the PI3K/AKT Signalling Pathway,” Cancer Gene Therapy 29, no. 3-4 (2022): 292-303.

[196] Q. Ni, H. Zhang, X. Shi, X. Li, “Exosomal lncRNA HCG18 Contributes to Cholangiocarcinoma Growth and Metastasis Through Mediating miR-424-5p/SOX9 Axis Through PI3K/AKT Pathway,” Cancer Gene Therapy 30, no. 4 (2023): 582-595.

[197] Q. Li, B. Li, C.-L. Lu, J-Ye Wang, M. Gao, W. Gao, “LncRNA LINC01857 Promotes Cell Growth and Diminishes Apoptosis via PI3K/mTOR Pathway and EMT Process by Regulating miR-141-3p/MAP4K4 Axis in Diffuse Large B-cell Lymphoma,” Cancer Gene Therapy 28, no. 9 (2021): 1046-1057.

[198] C. Lei, S. Li, Y. Fan, et al., “LncRNA DUXAP8 Induces Breast Cancer Radioresistance by Modulating the PI3K/AKT/mTOR Pathway and the EZH2-E-cadherin/RHOB Pathway,” Cancer Biology & Therapy 23, no. 1 (2022): 1-13.

[199] P. Su, L. Jiang, Y. Zhang, et al., “Crosstalk Between Tumor-associated Macrophages and Tumor Cells Promotes Chemoresistance via CXCL5/PI3K/AKT/mTOR Pathway in Gastric Cancer,” Cancer Cell International 22, no. 1 (2022): 290.

[200] Q. Wu, J. Ma, J. Wei, W. Meng, Y. Wang, M. Shi, “FOXD1-AS1 regulates FOXD1 Translation and Promotes Gastric Cancer Progression and Chemoresistance by Activating the PI3K/AKT/mTOR Pathway,” Molecular Oncology 15, no. 1 (2021): 299-316.

[201] S. Dong, S. Liang, Z. Cheng, et al., “ROS/PI3K/Akt and Wnt/β-catenin Signalings Activate HIF-1α-induced Metabolic Reprogramming to Impart 5-fluorouracil Resistance in Colorectal Cancer,” Journal of Experimental & Clinical Cancer Research 41, no. 1 (2022): 15.

[202] H. Li, X. Shen, M. Ma, et al., “ZIP10 drives Osteosarcoma Proliferation and Chemoresistance Through ITGA10-mediated Activation of the PI3K/AKT Pathway,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 340.

[203] W.-F. Liu, Q.-W. Zhang, B. Quan, et al., “Gas7 attenuates Hepatocellular Carcinoma Progression and Chemoresistance Through the PI3K/Akt Signaling Pathway,” Cell Signalling 112 (2023): 110908.

[204] Qi Wang, T. Cao, X. Zhang, et al., “ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8(+) T Cell Cytotoxicity,” Journal of Immunology Research 2022 (2022): 6863240.

[205] Z. Gao, J. Wu, X. Wu, J. Zheng, Y. Ou, “SRPX2 boosts Pancreatic Cancer Chemoresistance by Activating PI3K/AKT Axis,” Open medicine (Warsaw) 15, no. 1 (2020): 1072-1082.

[206] M‑De Fan, X. ‑. Y. Zhao, J‑Ni Qi, et al., “TRIM31 enhances Chemoresistance in Glioblastoma Through Activation of the PI3K/Akt Signaling Pathway,” Experimental and Therapeutic Medicine 20, no. 2 (2020): 802-809.

[207] T. Wu, Z. Jiao, Y. Li, et al., “HPRT1 Promotes Chemoresistance in Oral Squamous Cell Carcinoma via Activating MMP1/PI3K/Akt Signaling Pathway,” Cancers (Basel) 14, no. 4 (2022): 855.

[208] S. C. Tripathi, J. F. Fahrmann, M. Celiktas, et al., “MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway,” Cancer Research 77, no. 16 (2017): 4414-4425.

[209] H. Shao, J. Chen, A. Li, et al., “Salvigenin Suppresses Hepatocellular Carcinoma Glycolysis and Chemoresistance through Inactivating the PI3K/AKT/GSK-3β Pathway,” Applied Biochemistry and Biotechnology 195, no. 8 (2023): 5217-5237.

[210] P. Tian, D. Du, Li Yang, N. Zhou, L. Tao, “Lentinan Mitigates Pemetrexed Chemoresistance by the PI3K/Akt Pathway in Non-small Cell Lung Cancer,” Cell Biochemistry and Biophysics 82, no. 2 (2024): 1421-1431.

[211] O. A. Bamodu, H.-L. Chang, J.-R. Ong, W.-H. Lee, C.-T. Yeh, J.-T. Tsai, “Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma,” Cells 9, no. 3 (2020): 746.

[212] H. Deng, Y. Chen, Li Wang, et al., “PI3K/mTOR Inhibitors Promote G6PD Autophagic Degradation and Exacerbate Oxidative Stress Damage to Radiosensitize Small Cell Lung Cancer,” Cell Death & Disease 14, no. 10 (2023): 652.

[213] Y. Yuan, Hu Liao, Q. Pu, et al., “miR-410 Induces both Epithelial-mesenchymal Transition and Radioresistance Through Activation of the PI3K/mTOR Pathway in Non-small Cell Lung Cancer,” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 85.

[214] R. Sun, C. Chen, X. Deng, et al., “IL-11 Mediates the Radioresistance of Cervical Cancer Cells via the PI3K/Akt Signaling Pathway,” Journal of Cancer 12, no. 15 (2021): 4638-4647.

[215] Z.-X. Zhao, Y.-Q. Zhang, H. Sun, et al., “Calcipotriol Abrogates Cancer-associated Fibroblast-derived IL-8-mediated Oxaliplatin Resistance in Gastric Cancer Cells via Blocking PI3K/Akt Signaling,” Acta Pharmacologica Sinica 44, no. 1 (2023): 178-188.

[216] Y. Li, Z. Wang, J. Yang, et al., “CircTRIM1 encodes TRIM1-269aa to Promote Chemoresistance and Metastasis of TNBC via Enhancing CaM-dependent MARCKS Translocation and PI3K/AKT/mTOR Activation,” Molecular Cancer 23, no. 1 (2024): 102.

[217] L. Shi, W. Zhu, Y. Huang, et al., “Cancer-associated Fibroblast-derived Exosomal microRNA-20a Suppresses the PTEN/PI3K-AKT Pathway to Promote the Progression and Chemoresistance of Non-small Cell Lung Cancer,” Clinical and Translational Medicine 12, no. 7 (2022): e989.

[218] W. Jiang, X. Yang, K. Shi, et al., “MAD2 activates IGF1R/PI3K/AKT Pathway and Promotes Cholangiocarcinoma Progression by Interfering USP44/LIMA1 Complex,” Oncogene 42, no. 45 (2023): 3344-3357.

[219] J. Gu, W. Huang, X. Wang, et al., “Hsa-miR-3178/RhoB/PI3K/Akt, a Novel Signaling Pathway Regulates ABC Transporters to Reverse Gemcitabine Resistance in Pancreatic Cancer,” Molecular Cancer 21, no. 1 (2022): 112.

[220] A. A. Hassan, M. Artemenko, M. K. S. Tang, et al., “Ascitic Fluid Shear Stress in Concert With Hepatocyte Growth Factor Drive Stemness and Chemoresistance of Ovarian Cancer Cells via the c-Met-PI3K/Akt-miR-199a-3p Signaling Pathway,” Cell Death & Disease 13, no. 6 (2022): 537.

[221] K. J. Pridham, F. Shah, K. R. Hutchings, et al., “Connexin 43 Confers Chemoresistance Through Activating PI3K,” Oncogenesis 11, no. 1 (2022): 2.

[222] K. Lin, E. Zhou, T. Shi, et al., “m6A eraser FTO Impairs Gemcitabine Resistance in Pancreatic Cancer Through Influencing NEDD4 mRNA Stability by Regulating the PTEN/PI3K/AKT Pathway,” Journal of Experimental & Clinical Cancer Research 42, no. 1 (2023): 217.

[223] X. Zhang, N. Zou, W. Deng, et al., “HMGB1 induces Radioresistance Through PI3K/AKT/ATM Pathway in Esophageal Squamous Cell Carcinoma,” Molecular Biology Reports 49, no. 12 (2022): 11933-11945.

[224] X. Du, X. Zhang, J. Dong, et al., “Irradiation-induced Exosomal HMGB1 to Confer Radioresistance via the PI3K/AKT/FOXO3A Signaling Pathway in ESCC,” Journal of Translational Medicine 20, no. 1 (2022): 507.

[225] Y. Ma, X. Chen, T. Ding, et al., “KAT7 promotes Radioresistance Through Upregulating PI3K/AKT Signaling in Breast Cancer,” Journal of Radiation Research 64, no. 2 (2023): 448-456.

[226] Y. Zhang, L. Zheng, Yi Ding, et al., “MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma,” International Journal of Radiation and Oncology in Biology and Physics 92, no. 5 (2015): 1132-1140.

[227] Q. Chen, W. Zheng, L. Zhu, et al., “ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma,” Frontiers in Cell and Developmental Biology 8 (2020): 232.

[228] J. S. Bergholz, Q. Wang, Qi Wang, et al., “PI3Kβ controls Immune Evasion in PTEN-deficient Breast Tumours,” Nature 617, no. 7959 (2023): 139-146.

[229] N. Jiang, Q. Dai, X. Su, J. Fu, X. Feng, J. Peng, “Role of PI3K/AKT Pathway in Cancer: The Framework of Malignant Behavior,” Molecular Biology Reports 47, no. 6 (2020): 4587-4629.

[230] D. C. Collins, M. Chenard-Poirier, J. S. Lopez, “The PI3K Pathway at the Crossroads of Cancer and the Immune System: Strategies for next Generation Immunotherapy Combinations,” Current Cancer Drug Targets 18, no. 4 (2018): 355-364.

[231] J. S. O'Donnell, D. Massi, M. W. L. Teng, M. Mandala, “PI3K-AKT-mTOR Inhibition in Cancer Immunotherapy, Redux,” Seminars in Cancer Biology 48 (2018): 91-103.

[232] F. Dituri, A. Mazzocca, G. Giannelli, S. Antonaci, “PI3K Functions in Cancer Progression, Anticancer Immunity and Immune Evasion by Tumors,” Journal of Immunology Research 2011, no. 1 (2011): 947858.

[233] A. H. Mohseni, V. Casolaro, L. G. Bermúdez-Humarán, H. Keyvani, S. Taghinezhad-S, “Modulation of the PI3K/Akt/mTOR Signaling Pathway by Probiotics as a Fruitful Target for Orchestrating the Immune Response,” Gut Microbes 13, no. 1 (2021): 1886844.

[234] S. Mafi, B. Mansoori, S. Taeb, et al., “mTOR-mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment,” Frontiers in Immunology 12 (2022): 774103.

[235] X. Zhang, Y. Zeng, Q. Qu, et al., “PD-L1 Induced by IFN-γ From Tumor-associated Macrophages via the JAK/STAT3 and PI3K/AKT Signaling Pathways Promoted Progression of Lung Cancer,” International Journal of Clinical Oncology 22, no. 6 (2017): 1026-1033.

[236] Y. Liu, C. Huang, M. Luo, et al., “C1q(+) Macrophage-Tumor Cell Interaction Promoted Tumorigenesis via GPR17/PI3K/AKT Pathway Induced DNA Hypermethylation in Nasopharyngeal Carcinoma,” Advanced Science (Weinheim) (2025): e2503434.

[237] X. Sun, J. Zhang, B. Dong, et al., “Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor-Associated Macrophage,” Advanced Science (Weinheim) 12, no. 1 (2025): e2400367.

[238] D. Li, L. Xia, P. Huang, et al., “Cancer-associated Fibroblast-secreted IGFBP7 Promotes Gastric Cancer by Enhancing Tumor Associated Macrophage Infiltration via FGF2/FGFR1/PI3K/AKT Axis,” Cell Death Discovery 9, no. 1 (2023): 17.

[239] Li Ying, Z. Zhu, Z. Xu, et al., “Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform,” PLoS ONE 10, no. 6 (2015): e0129593.

[240] Y. Jin, Q. Meng, B. Zhang, et al., “Cancer-associated Fibroblasts-derived Exosomal miR-3656 Promotes the Development and Progression of Esophageal Squamous Cell Carcinoma via the ACAP2/PI3K-AKT Signaling Pathway,” International Journal of Biological Sciences 17, no. 14 (2021): 3689-3701.

[241] L. Sun, M. Ke, X. Wang, et al., “FAP(high) α-SMA(low) Cancer-associated Fibroblast-derived SLPI Protein Encapsulated in Extracellular Vesicles Promotes Ovarian Cancer Development via Activation of PI3K/AKT and Downstream Signaling Pathways,” Molecular Carcinogenesis 61, no. 10 (2022): 910-923.

[242] W. Cacheux, A. Lièvre, S. Richon, et al., “Interaction Between IGF2-PI3K Axis and Cancer-associated-fibroblasts Promotes Anal Squamous Carcinogenesis,” International Journal of Cancer 145, no. 7 (2019): 1852-1859.

[243] B. A. Cardoso, et al., “CASZ1 upregulates PI3K-AKT-mTOR Signaling and Promotes T-cell Acute Lymphoblastic Leukemia,” Haematologica 109, no. 6 (2024): 1713-1725.

[244] X. Sun, X. Zheng, Xu Zhang, Y. Zhang, G. Luo, “Exosomal microRNA-23b-3p From Bone Marrow Mesenchymal Stem Cells Maintains T Helper/Treg Balance by Downregulating the PI3k/Akt/NF-κB Signaling Pathway in Intracranial Aneurysm,” Brain Research Bulletin 165 (2020): 305-315.

[245] S. Heller, S. Glaeske, K. Gluske, et al., “Pan-PI3K Inhibition With Copanlisib Overcomes Treg- and M2-TAM-mediated Immune Suppression and Promotes Anti-tumor Immune Responses,” Clinical and Experimental Medicine 23, no. 8 (2023): 5445-5461.

[246] M. C. Herrero-Sánchez, C. Rodríguez-Serrano, J. Almeida, et al., “Targeting of PI3K/AKT/mTOR Pathway to Inhibit T Cell Activation and Prevent Graft-versus-host Disease Development,” Journal of Hematology & Oncology 9, no. 1 (2016): 113.

[247] L. Rohrbacher, B. Brauchle, A. Ogrinc Wagner, M. Von Bergwelt-Baildon, V. L. Bücklein, M. Subklewe, “The PI3K∂-Selective Inhibitor Idelalisib Induces T- and NK-Cell Dysfunction Independently of B-Cell Malignancy-Associated Immunosuppression,” Frontiers in Immunology 12 (2021): 608625.

[248] S. Isoyama, S. Mori, D. Sugiyama, et al., “Cancer Immunotherapy With PI3K and PD-1 Dual-blockade via Optimal Modulation of T Cell Activation Signal,” Journal for ImmunoTherapy of Cancer 9, no. 8 (2021): e002279.

[249] Y. Xie, D. W. Zhong, “AEG-1 Is Associated With Hypoxia-induced Hepatocellular Carcinoma Chemoresistance via Regulating PI3K/AKT/HIF-1alpha/MDR-1 Pathway,” EXCLI Journal 15 (2016): 745-757.

[250] A. Miyasaka, K. Oda, Y. Ikeda, et al., “PI3K/mTOR Pathway Inhibition Overcomes Radioresistance via Suppression of the HIF1-α/VEGF Pathway in Endometrial Cancer,” Gynecologic Oncology 138, no. 1 (2015): 174-180.

[251] J. Fang, C. Xia, Z. Cao, J. Z. Zheng, E. Reed, B.-H. Jiang, “Apigenin Inhibits VEGF and HIF-1 Expression via PI3K/AKT/p70S6K1 and HDM2/p53 Pathways,” Faseb Journal 19, no. 3 (2005): 342-353.

[252] T. R. Kim, E. W. Cho, SGi Paik, InG Kim, “Hypoxia-induced SM22α in A549 Cells Activates the IGF1R/PI3K/Akt Pathway, Conferring Cellular Resistance Against Chemo- and Radiation Therapy,” Febs Letters 586, no. 4 (2012): 303-309.

[253] C. Li, J. Li, Y. Li, et al., “Isorhamnetin Promotes MKN-45 Gastric Cancer Cell Apoptosis by Inhibiting PI3K-Mediated Adaptive Autophagy in a Hypoxic Environment,” Journal of Agricultural and Food Chemistry 69, no. 29 (2021): 8130-8143.

[254] Y. Tian, Lu Zhao, Z. Gui, et al., “PI3K/AKT Signaling Activates HIF1α to Modulate the Biological Effects of Invasive Breast Cancer With Microcalcification,” NPJ Breast Cancer 9, no. 1 (2023): 93.

[255] K. Patra, S. Jana, A. Sarkar, D. P. Mandal, S. Bhattacharjee, “The Inhibition of Hypoxia-induced Angiogenesis and Metastasis by Cinnamaldehyde Is Mediated by Decreasing HIF-1α Protein Synthesis via PI3K/Akt Pathway,” Biofactors 45, no. 3 (2019): 401-415.

[256] H. Wang, L. Zhao, L. T. Zhu, et al., “Wogonin Reverses Hypoxia Resistance of human Colon Cancer HCT116 Cells via Downregulation of HIF-1α and Glycolysis, by Inhibiting PI3K/Akt Signaling Pathway,” Molecular Carcinogenesis 53, no. Suppl 1 (2014): E107-E118.

[257] J. Zhang, J. Xu, Y. Dong, Bo Huang, “Down-regulation of HIF-1α Inhibits the Proliferation, Migration, and Invasion of Gastric Cancer by Inhibiting PI3K/AKT Pathway and VEGF Expression,” Bioscience Reports 38, no. 6 (2018): BSR20180741.

[258] G. Lin, R. Gai, Z. Chen, et al., “The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Prevents Epithelial-mesenchymal Transition Induced by Hypoxia and TGF-β1,” European Journal of Pharmacology 729 (2014): 45-53.

[259] X. Liu, L. Liu, K. Chen, L. Sun, W. Li, S. Zhang, “Huaier Shows Anti-cancer Activities by Inhibition of Cell Growth, Migration and Energy Metabolism in Lung Cancer Through PI3K/AKT/HIF-1α Pathway,” Journal of Cellular and Molecular Medicine 25, no. 4 (2021): 2228-2237.

[260] Z. Shi, S. K. Y. To, S. Zhang, et al., “Hypoxia-induced Nur77 Activates PI3K/Akt Signaling via Suppression of Dicer/Let-7i-5p to Induce Epithelial-to-mesenchymal Transition,” Theranostics 11, no. 7 (2021): 3376-3391.

[261] W.-J. Zhu, H.-H. Huang, Y.-F. Feng, et al., “Hypoxia-induced miR-9 Expression Promotes Ovarian Cancer Progression via Activating PI3K/AKT/mTOR/GSK3β Signaling Pathway,” Neoplasma 70, no. 2 (2023): 216-228.

[262] J. Du, R. Xu, Z. Hu, et al., “PI3K and ERK-induced Rac1 Activation Mediates Hypoxia-induced HIF-1α Expression in MCF-7 Breast Cancer Cells,” PLoS ONE 6, no. 9 (2011): e25213.

[263] J. Wang, H.-Y. Wang, Y. Shen, et al., “A Novel Small-molecule PI3K/Akt Signaling Inhibitor, W934, Exhibits Potent Antitumor Efficacy in A549 Non-small-cell Lung Cancer,” Anti-Cancer Drugs 30, no. 9 (2019): 900-908.

[264] G. Li, Z. Song, Yi Ru, et al., “Small-molecule Nanoprodrug With High Drug Loading and EGFR, PI3K/AKT Dual-inhibiting Properties for Bladder Cancer Treatment,” Exploration (Beijing) 3, no. 5 (2023): 20220141.

[265] F. M. Shang, J. Li, “A Small-molecule Antagonist of CXCR1 and CXCR2 Inhibits Cell Proliferation, Migration and Invasion in Melanoma via PI3K/AKT Pathway,” Medicina Clinica 152, no. 11 (2019): 425-430.

[266] S. Peng, H. Li, W. Cui, et al., “Design, Synthesis and Biological Evaluation of a Novel PSMA-PI3K Small Molecule Drug Conjugate,” RSC Medicinal Chemistry 15, no. 10 (2024): 3485-3494.

[267] A. K. Qazi, A. Hussain, S. Khan, et al., “Quinazoline Based Small Molecule Exerts Potent Tumour Suppressive Properties by Inhibiting PI3K/Akt/FoxO3a Signalling in Experimental Colon Cancer,” Cancer Letters 359, no. 1 (2015): 47-56.

[268] Y. Li, X. Xie, S. Liao, et al., “A011, a Novel Small-molecule Ligand of σ(2) Receptor, Potently Suppresses Breast Cancer Progression via Endoplasmic Reticulum Stress and Autophagy,” Biomedicine & Pharmacotherapy 152 (2022): 113232.

[269] X. Bao, W. Zheng, N. H. Sugi, et al., “Small Molecule Schweinfurthins Selectively Inhibit Cancer Cell Proliferation and mTOR/AKT Signaling by Interfering With Trans-Golgi-network Trafficking,” Cancer Biology & Therapy 16, no. 4 (2015): 589-601.

[270] B. F. Clem, A. L. Clem, A. Yalcin, et al., “A Novel Small Molecule Antagonist of Choline Kinase-α That Simultaneously Suppresses MAPK and PI3K/AKT Signaling,” Oncogene 30, no. 30 (2011): 3370-3380.

[271] G. I. Shapiro, K. M. Bell-Mcguinn, J. R. Molina, et al., “First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients With Advanced Cancer,” Clinical Cancer Research 21, no. 8 (2015): 1888-1895.

[272] Z. Wang, J. Lv, X. Li, Q. Lin, “The Flavonoid Astragalin Shows Anti-tumor Activity and Inhibits PI3K/AKT Signaling in Gastric Cancer,” Chemical Biology and Drug Design 98, no. 5 (2021): 779-786.

[273] D. Jiang, J. Xu, S. Liu, et al., “Rosmanol Induces Breast Cancer Cells Apoptosis by Regulating PI3K/AKT and STAT3/JAK2 Signaling Pathways,” Oncology Letters 22, no. 2 (2021): 631.

[274] R. Wang, R. Li, H. Yang, et al., “Flavokawain C Inhibits Proliferation and Migration of Liver Cancer Cells Through FAK/PI3K/AKT Signaling Pathway,” Journal of Cancer Research and Clinical Oncology 150, no. 3 (2024): 117.

[275] Yi Zuo, C.-Z. Zhang, Q. Ren, et al., “Activation of Mitochondrial-associated Apoptosis Signaling Pathway and Inhibition of PI3K/Akt/mTOR Signaling Pathway by Voacamine Suppress Breast Cancer Progression,” Phytomedicine 99 (2022): 154015.

[276] H. Li, Y. Zhang, X. Lan, et al., “Halofuginone Sensitizes Lung Cancer Organoids to Cisplatin via Suppressing PI3K/AKT and MAPK Signaling Pathways,” Frontiers in Cell and Developmental Biology 9 (2021): 773048.

[277] H. Liang, G. Yin, G. Shi, Z. Liu, X. Liu, J. Li, “Echinacoside Regulates PI3K/AKT/HIF-1α/VEGF Cross Signaling Axis in Proliferation and Apoptosis of Breast Cancer,” Analytical Biochemistry 684 (2024): 115360.

[278] J. Liu, Ni Tang, Ni Liu, P. Lei, F. Wang, “Echinacoside Inhibits the Proliferation, Migration, Invasion and Angiogenesis of Ovarian Cancer Cells Through PI3K/AKT Pathway,” Journal of Molecular Histology 53, no. 2 (2022): 493-502.

[279] S. Hu, J. Yin, S. Yan, et al., “Chaetocochin J, an Epipolythiodioxopiperazine Alkaloid, Induces Apoptosis and Autophagy in Colorectal Cancer via AMPK and PI3K/AKT/mTOR Pathways,” Bioorganic Chemistry 109 (2021): 104693.

[280] Y. S. Won, K. I. Seo, “Lupiwighteone Induces Caspase-dependent and -independent Apoptosis on human Breast Cancer Cells via Inhibiting PI3K/Akt/mTOR Pathway,” Food and Chemical Toxicology 135 (2020): 110863.

[281] C. Xu, C. Zhang, K. Ganesan, et al., “Anti-migratory Properties of Cryoprotective Isoliquiritigenin-zein Phosphatidylcholine Nanoparticles Prevent Triple-negative Breast Cancer Through PI3K-mTOR and MMP2/9 Pathways,” Current Medicinal Chemistry (2023).

[282] S. Sundram, S. Baskar, A. Subramanian, “Green Synthesized Nickel Doped Cobalt Ferrite Nanoparticles Exhibit Antibacterial Activity and Induce Reactive Oxygen Species Mediated Apoptosis in MCF-7 Breast Cancer Cells Through Inhibition of PI3K/Akt/mTOR Pathway,” Environmental Toxicology 37, no. 12 (2022): 2877-2888.

[283] X.-J. Mi, H. S. Choi, H. Perumalsamy, et al., “Biosynthesis and Cytotoxic Effect of Silymarin-functionalized Selenium Nanoparticles Induced Autophagy Mediated Cellular Apoptosis via Downregulation of PI3K/Akt/mTOR Pathway in Gastric Cancer,” Phytomedicine 99 (2022): 154014.

[284] Q. Yin, Q. Zhou, J. Hu, et al., “Fabrication of Bimetallic Ag@ZnO Nanocomposite and Its Anti-cancer Activity on Cervical Cancer via Impeding PI3K/AKT/mTOR Pathway,” Journal of Trace Elements in Medicine and Biology 84 (2024): 127437.

[285] R. J. Brisson, S. Kochanny, S. Arshad, et al., “A Pilot Study of the Pan-class I PI3K Inhibitor buparlisib in Combination With cetuximab in Patients With Recurrent or Metastatic Head and Neck Cancer,” Head & Neck 41, no. 11 (2019): 3842-3849.

[286] R. D. Baird, A. G. J. Van Rossum, M. Oliveira, et al., “POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined With Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients,” Clinical Cancer Research 25, no. 22 (2019): 6598-6605.

[287] Z. A. Wainberg, M. Alsina, H. P. Soares, et al., “A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer,” Targeted Oncology 12, no. 6 (2017): 775-785.

[288] J. F. Vansteenkiste, J.-L. Canon, F. De Braud, et al., “Safety and Efficacy of Buparlisib (BKM120) in Patients With PI3K Pathway-Activated Non-Small Cell Lung Cancer: Results From the Phase II BASALT-1 Study,” Journal of Thoracic Oncology 10, no. 9 (2015): 1319-1327.

[289] R. K. Basho, M. Gilcrease, R. K. Murthy, et al., “Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer: Evidence from a Phase 1 Trial of mTOR Inhibition in Combination with Liposomal Doxorubicin and Bevacizumab,” JAMA Oncology 3, no. 4 (2017): 509-515.

[290] V. Subbiah, N. Coleman, S. A. Piha-Paul, et al., “Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228/TAK-228) in Combination With Metformin in Patients With mTOR/AKT/PI3K Pathway Alterations and Advanced Solid Malignancies,” Cancer Research Communications 4, no. 2 (2024): 378-387.

[291] K. Blackwell, H. Burris, P. Gomez, et al., “Phase I/II Dose-escalation Study of PI3K Inhibitors pilaralisib or voxtalisib in Combination With letrozole in Patients With Hormone-receptor-positive and HER2-negative Metastatic Breast Cancer Refractory to a Non-steroidal Aromatase Inhibitor,” Breast Cancer Research and Treatment 154, no. 2 (2015): 287-297.

[292] J. Rodon, A. Pérez-Fidalgo, I. E. Krop, et al., “Phase 1/1b Dose Escalation and Expansion Study of BEZ235, a Dual PI3K/mTOR Inhibitor, in Patients With Advanced Solid Tumors Including Patients With Advanced Breast Cancer,” Cancer Chemotheraphy and Pharmacology 82, no. 2 (2018): 285-298.

[293] B. D. Lehmann, V. G. Abramson, M. E. Sanders, et al., “TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients With AR(+) Metastatic Triple-Negative Breast Cancer,” Clinical Cancer Research 26, no. 9 (2020): 2111-2123.

[294] E. G. Chiorean, V. Picozzi, C.-P. Li, et al., “Efficacy and Safety of abemaciclib Alone and With PI3K/mTOR Inhibitor LY3023414 or Galunisertib versus Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma: A Randomized Controlled Trial,” Cancer Medicine 12, no. 20 (2023): 20353-20364.

[295] H. S. Rugo, F. André, T. Yamashita, et al., “Time Course and Management of Key Adverse Events During the Randomized Phase III SOLAR-1 Study of PI3K Inhibitor alpelisib plus fulvestrant in Patients With HR-positive Advanced Breast Cancer,” Annals of Oncology 31, no. 8 (2020): 1001-1010.

[296] A. J. Mcree, P. K. Marcom, D. T. Moore, et al., “A Phase I Trial of the PI3K Inhibitor Buparlisib Combined with Capecitabine in Patients with Metastatic Breast Cancer,” Clinical Breast Cancer 18, no. 4 (2018): 289-297.

[297] M. Martín, A. Chan, L. Dirix, et al., “A Randomized Adaptive Phase II/III Study of buparlisib, a Pan-class I PI3K Inhibitor, Combined With paclitaxel for the Treatment of HER2- advanced Breast Cancer (BELLE-4),” Annals of Oncology 28, no. 2 (2017): 313-320.

[298] X. X. Wei, A. C. Hsieh, W. Kim, et al., “A Phase I Study of Abiraterone Acetate Combined With BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer,” The Oncologist 22, no. 5 (2017): 503. e43.

[299] J. C. Bendell, A. M. Varghese, D. M. Hyman, et al., “A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients With Advanced Cancer,” Clinical Cancer Research 24, no. 14 (2018): 3253-3262.

[300] P. A. Jänne, R. B. Cohen, A. D. Laird, et al., “Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 (XL765) in Combination With erlotinib in Patients With Advanced Solid Tumors,” Journal of Thoracic Oncology 9, no. 3 (2014): 316-323.

[301] A. Younes, J. G. Berdeja, M. R. Patel, et al., “Safety, Tolerability, and Preliminary Activity of CUDC-907, a First-in-class, Oral, Dual Inhibitor of HDAC and PI3K, in Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma: An Open-label, Dose-escalation, Phase 1 Trial,” The Lancet Oncology 17, no. 5 (2016): 622-631.

[302] P. N. Morcos, J. Schlender, R. Burghaus, et al., “Model-informed Approach to Support Pediatric Dosing for the Pan-PI3K Inhibitor copanlisib in Children and Adolescents With Relapsed/Refractory Solid Tumors,” Clinical and Translational Science 16, no. 7 (2023): 1197-1209.

[303] M. M. Rubinstein, D. M. Hyman, I. Caird, et al., “Phase 2 Study of LY3023414 in Patients With Advanced Endometrial Cancer Harboring Activating Mutations in the PI3K Pathway,” Cancer 126, no. 6 (2020): 1274-1282.

[304] D. C. Starks, L. Rojas-Espaillat, T. Meissner, C. B. Williams, “Phase I Dose Escalation Study of Dual PI3K/mTOR Inhibition by Sapanisertib and Serabelisib in Combination With paclitaxel in Patients With Advanced Solid Tumors,” Gynecologic Oncology 166, no. 3 (2022): 403-409.

[305] G. Marret, N. Isambert, K. Rezai, et al., “Phase I Trial of copanlisib, a Selective PI3K Inhibitor, in Combination With cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma,” Investigational New Drugs 39, no. 6 (2021): 1641-1648.

[306] J. J. Wheler, S. L. Moulder, A. Naing, et al., “Anastrozole and Everolimus in Advanced Gynecologic and Breast Malignancies: Activity and Molecular Alterations in the PI3K/AKT/mTOR Pathway,” Oncotarget 5, no. 10 (2014): 3029-3038.

[307] A. Wicki, N. Brown, A. Xyrafas, et al., “First-in human, Phase 1, Dose-escalation Pharmacokinetic and Pharmacodynamic Study of the Oral Dual PI3K and mTORC1/2 Inhibitor PQR309 in Patients With Advanced Solid Tumors (SAKK 67/13),” European Journal of Cancer 96 (2018): 6-16.

[308] S. Di Cosimo, S. Sathyanarayanan, J. C. Bendell, et al., “Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial,” Clinical Cancer Research 21, no. 1 (2015): 49-59.

[309] R. J. Amato, G. Wilding, G. Bubley, J. Loewy, F. Haluska, M. E. Gross, “Safety and Preliminary Efficacy Analysis of the mTOR Inhibitor ridaforolimus in Patients With Taxane-treated, Castration-resistant Prostate Cancer,” Clinical Genitourinary Cancer 10, no. 4 (2012): 232-238.

[310] E. M. Gordon, N. L. Angel, N. Omelchenko, et al., “A Phase I/II Investigation of Safety and Efficacy of Nivolumab and nab-Sirolimus in Patients with a Variety of Tumors with Genetic Mutations in the mTOR Pathway,” Anticancer Research 43, no. 5 (2023): 1993-2002.

[311] G. Jerusalem, A. Fasolo, V. Dieras, et al., “Phase I Trial of Oral mTOR Inhibitor everolimus in Combination With Trastuzumab and Vinorelbine in Pre-treated Patients With HER2-overexpressing Metastatic Breast Cancer,” Breast Cancer Research and Treatment 125, no. 2 (2011): 447-455.

[312] S. Kordes, H. J. Klümpen, M. J. Weterman, J. H. M. Schellens, D. J. Richel, J. W. Wilmink, “Phase II Study of Capecitabine and the Oral mTOR Inhibitor Everolimus in Patients With Advanced Pancreatic Cancer,” Cancer Chemotheraphy and Pharmacology 75, no. 6 (2015): 1135-1141.

[313] S. A. Piha-Paul, C. Tseng, H. T. Tran, et al., “Phase I Trial of the Combination of the Pan-ErbB Inhibitor neratinib and mTOR Inhibitor everolimus in Advanced Cancer Patients With ErbB family Gene Alterations,” ESMO Open 10, no. 2 (2025): 104136.

[314] A. C. De Melo, R. Grazziotin-Reisner, F. Erlich, et al., “A Phase I Study of mTOR Inhibitor everolimus in Association With Cisplatin and Radiotherapy for the Treatment of Locally Advanced Cervix Cancer: PHOENIX I,” Cancer Chemotheraphy and Pharmacology 78, no. 1 (2016): 101-109.

[315] J. Bosch-Barrera, P. Estévez-García, P. Martín-Martorell, et al., “ENDOLUNG Trial, Part II. A Phase II Study of the Akt/mTOR Inhibitor and Autophagy Inducer Ibrilatazar (ABTL0812) in Combination With Paclitaxel/Carboplatin in Patients With Squamous Non-small Cell Lung Cancer,” Lung Cancer 201 (2025): 108105.

[316] D. J. Mchugh, J. Chudow, M. Denunzio, et al., “A Phase I Trial of IGF-1R Inhibitor Cixutumumab and mTOR Inhibitor Temsirolimus in Metastatic Castration-resistant Prostate Cancer,” Clinical Genitourinary Cancer 18, no. 3 (2020): 171-178. e2.

[317] P. Heudel, J.-S. Frenel, C. Dalban, et al., “Safety and Efficacy of the mTOR Inhibitor, Vistusertib, Combined with Anastrozole in Patients with Hormone Receptor-Positive Recurrent or Metastatic Endometrial Cancer: The VICTORIA Multicenter, Open-label, Phase 1/2 Randomized Clinical Trial,” JAMA Oncology 8, no. 7 (2022): 1001-1009.

[318] Y. Fujiwara, A. Kuchiba, T. Koyama, et al., “Infection Risk With PI3K-AKT-mTOR Pathway Inhibitors and Immune Checkpoint Inhibitors in Patients With Advanced Solid Tumours in Phase I Clinical Trials,” ESMO Open 5, no. 2 (2020): e000653.

[319] P. Schmid, S. E. Pinder, D. Wheatley, et al., “Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared with Anastrozole Alone in Patients with Estrogen Receptor-Positive Breast Cancer,” Journal of Clinical Oncology 34, no. 17 (2016): 1987-1994.

[320] P. L. Bedard, J. Tabernero, F. Janku, et al., “A Phase Ib Dose-escalation Study of the Oral Pan-PI3K Inhibitor buparlisib (BKM120) in Combination With the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients With Selected Advanced Solid Tumors,” Clinical Cancer Research 21, no. 4 (2015): 730-738.

[321] U. Banerji, E. J. Dean, J. A. Pérez-Fidalgo, et al., “A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers,” Clinical Cancer Research 24, no. 9 (2018): 2050-2059.

[322] B. R. Davies, H. Greenwood, P. Dudley, et al., “Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity With Genetic Background,” Molecular Cancer Therapeutics 11, no. 4 (2012): 873-887.

[323] K. Behbakht, M. W. Sill, K. M. Darcy, et al., “Phase II Trial of the mTOR Inhibitor, Temsirolimus and Evaluation of Circulating Tumor Cells and Tumor Biomarkers in Persistent and Recurrent Epithelial Ovarian and Primary Peritoneal Malignancies: A Gynecologic Oncology Group Study,” Gynecologic Oncology 123, no. 1 (2011): 19-26.

[324] J. Moroney, S. Fu, S. Moulder, et al., “Phase I Study of the Antiangiogenic Antibody bevacizumab and the mTOR/Hypoxia-inducible Factor Inhibitor temsirolimus Combined With Liposomal Doxorubicin: Tolerance and Biological Activity,” Clinical Cancer Research 18, no. 20 (2012): 5796-5805.

[325] E. Adib, K. Klonowska, K. Giannikou, et al., “Phase II Clinical Trial of Everolimus in a Pan-Cancer Cohort of Patients With mTOR Pathway Alterations,” Clinical Cancer Research 27, no. 14 (2021): 3845-3853.

[326] R. Rangwala, Y. C. Chang, J. Hu, et al., “Combined MTOR and Autophagy Inhibition: Phase I Trial of Hydroxychloroquine and Temsirolimus in Patients With Advanced Solid Tumors and Melanoma,” Autophagy 10, no. 8 (2014): 1391-1402.

[327] H. Park, I. Garrido-Laguna, A. Naing, et al., “Phase I Dose-escalation Study of the mTOR Inhibitor sirolimus and the HDAC Inhibitor Vorinostat in Patients With Advanced Malignancy,” Oncotarget 7, no. 41 (2016): 67521-67531.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.