Recent progress on tyrosine kinase inhibitors resistance in renal cell carcinoma: another brick in the wall?

Abstract

Renal cell carcinoma (RCC), the predominant form of kidney cancer, accounts for 90% of cases and poses significant clinical challenges due to frequent late-stage or metastatic presentation. Based on literature and surveillance data from 2020 to 2025, despite therapeutic advancements, metastatic RCC still exhibits a dismal 5-year survival rate. While tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor/platelet-derived growth factor pathways have been a cornerstone of RCC treatment, their efficacy is limited by acquired resistance, necessitating novel strategies to improve patient outcomes. This review synthesizes advancements from 2020 to 2025 in understanding and overcoming TKI resistance in RCC. We explored emerging mechanisms of resistance, including tumor microenvironment remodeling, metabolic reprogramming, and activation of alternative survival pathways. Furthermore, we evaluated innovative therapeutic approaches. By consolidating recent insights, this review highlights promising strategies to circumvent resistance and underscores the importance of personalized, mechanism-driven therapies. Our analysis aims to inform future research directions and clinical translation, ultimately advancing the management of TKI-resistant RCC.

Keywords

Tyrosine kinase inhibitors (TKIs) / renal cell carcinoma (RCC) / drug resistance

References

[1] Siegel RL,Msph ANG,Dvm AJ.Cancer statistics, 2025. PMCID:PMC11745215

[2] Young M,Beltran L.Renal cell carcinoma.Lancet2024;404:476-91

[3] Bukavina L,Bray F.Epidemiology of renal cell carcinoma: 2022 update.Eur Urol2022;82:529-42

[4] Rose TL.Renal cell carcinoma: a review.JAMA2024;332:1001-10 PMCID:PMC11790279

[5] Usher-Smith J,Rossi SH.Current evidence on screening for renal cancer.Nat Rev Urol2020;17:637-42 PMCID:PMC7610655

[6] Rizzo M,Tibollo V,Quaglini S.Clinical outcome predictors for metastatic renal cell carcinoma: a retrospective multicenter real-life case series. PMCID:PMC11225140

[7] Gupta K,Li JZ,Charbonneau C.Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review.Cancer Treat Rev2008;34:193-205

[8] Ali O,Kawamoto S.Recurrent renal cell carcinoma following nephrectomy and ablation therapy: radiology perspective.Eur J Radiol2018;107:134-42

[9] Tur J.The renal cell carcinoma drug market.Nat Rev Drug Discov2024;23:16-7

[10] Jonasch E,Rathmell WK.Clear cell renal cell carcinoma ontogeny and mechanisms of lethality.Nat Rev Nephrol2021;17:245-61 PMCID:PMC8172121

[11] Cotta BH,Cieslik M.Current landscape of genomic biomarkers in clear cell renal cell carcinoma.Eur Urol2023;84:166-75 PMCID:PMC11175840

[12] Rathmell WK,Van Veldhuizen PJ.Management of metastatic clear cell renal cell carcinoma: ASCO guideline.J Clin Oncol2022;40:2957-95

[13] Barragan-Carrillo R,Saliby RM.First and second-line treatments in metastatic renal cell carcinoma.Eur Urol2025;87:143-54

[14] Zhao Y,Raza A.Tyrosine kinase inhibitors and their unique therapeutic potentialities to combat cancer.Int J Biol Macromol2021;168:22-37

[15] Sharma R,Myers M,Prithviraj P.Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma.J Exp Clin Cancer Res2021;40:186 PMCID:PMC8183071

[16] Marona P,Kwapisz O.Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation.Cell Death Dis2022;13:814 PMCID:PMC9500022

[17] Davis MI,Herrgard S.Comprehensive analysis of kinase inhibitor selectivity.Nat Biotechnol2011;29:1046-51

[18] Liu T,Burley SK.BindingDB in 2024: a FAIR knowledgebase of protein-small molecule binding data.Nucleic Acids Res2025;53:D1633-44 PMCID:PMC11701568

[19] Yakes FM,Tan J.Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.Mol Cancer Ther2011;10:2298-308

[20] Saha D,Lakkaniga NR.Targeting rearranged during transfection in cancer: a perspective on small-molecule inhibitors and their clinical development.J Med Chem2021;64:11747-73 PMCID:PMC9697126

[21] Matsui J,Funahashi Y.E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition.Int J Cancer2008;122:664-71

[22] Karaman MW,Treiber DK.A quantitative analysis of kinase inhibitor selectivity.Nat Biotechnol2008;26:127-32

[23] Deeks ED.Pazopanib: in advanced soft tissue sarcoma.Drugs2012;72:2129-40

[24] Mendel DB,Xin X.In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.Clin Cancer Res2003;9:327-37

[25] Wang Y,Gong L.Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics.Br J Pharmacol2023;180:2937-55

[26] Zhou L,Sun M.Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma.Oncogene2016;35:2687-97 PMCID:PMC4791213

[27] Qu L,Chen C.Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA.Cancer Cell2016;29:653-68

[28] Rosenzweig SA.Acquired resistance to drugs targeting receptor tyrosine kinases.Biochem Pharmacol2012;83:1041-8 PMCID:PMC3299940

[29] Fukumoto W,Horike SI.Potential therapeutic target secretogranin II might cooperate with hypoxia-inducible factor 1α in sunitinib-resistant renal cell carcinoma.Cancer Sci2023;114:3946-56 PMCID:PMC10551594

[30] He H,Wang W.The SIRT7-mediated deacetylation of CHD1L amplifies HIF-2α-dependent signal that drives renal cell carcinoma progression and sunitinib resistance.Cell Biosci2023;13:166 PMCID:PMC10493023

[31] Ge X,Yin J.Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.Mol Cell2022;82:1249-60.e7

[32] Xiong W,Yu H,Yi L.RRM2 regulates sensitivity to sunitinib and PD-1 blockade in renal cancer by stabilizing ANXA1 and activating the AKT pathway.Adv Sci2021;8:e2100881 PMCID:PMC8456228

[33] Liu S,Zhang J.IKBKE regulates renal cell carcinoma progression and sunitinib resistance through the RRM2-AKT pathway.Int J Biol Sci2024;20:6146-61 PMCID:PMC11628342

[34] Fang L,Zang Y.HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT.Carbohydr Polym2019;223:115109

[35] Bouchalova P,Lapcik P.Transgelin contributes to a poor response of metastatic renal cell carcinoma to sunitinib treatment.Biomedicines2021;9:1145 PMCID:PMC8467952

[36] Xie Y,Chen Z.Establishment of sunitinib-resistant xenograft model of renal cell carcinoma and the identification of drug-resistant hub genes and pathways.Drug Des Devel Ther2021;15:5061-74 PMCID:PMC8687523

[37] Stokes ME,Fujisawa S.PERK inhibition by HC-5404 sensitizes renal cell carcinoma tumor models to antiangiogenic tyrosine kinase inhibitors.Clin Cancer Res2023;29:4870-82 PMCID:PMC10690095

[38] Wang Y,Wang P,Lin W.Circular RNAs in renal cell carcinoma: implications for tumorigenesis, diagnosis, and therapy.Mol Cancer2020;19:149 PMCID:PMC7559063

[39] Qin S,Wang P.Molecular mechanism of circRNAs in drug resistance in renal cell carcinoma.Cancer Cell Int2022;22:369 PMCID:PMC9686082

[40] Huang KB,Shu GN.Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/lysophosphatidic acid axis.Cancer Lett2021;523:121-34

[41] Shou Y,Wang Q.circPTPN12 promotes the progression and sunitinib resistance of renal cancer via hnRNPM/IL-6/STAT3 pathway.Cell Death Dis2023;14:232 PMCID:PMC10066201

[42] Liu Y,Shou Y.circRARS synergises with IGF2BP3 to regulate RNA methylation recognition to promote tumour progression in renal cell carcinoma.Clin Transl Med2023;13:e1512 PMCID:PMC10711645

[43] Liu Y,Fang Y,Luo Z.Non-coding RNAs in renal cell carcinoma: implications for drug resistance.Biomed Pharmacother2023;164:115001

[44] Gao X,Zhang C.The emerging role of long non-coding RNAs in renal cell carcinoma progression and clinical therapy via targeting metabolic regulation.Front Pharmacol2023;14:1122065 PMCID:PMC10034124

[45] Pan Y,Shu G.Extracellular vesicle-mediated transfer of lncRNA IGFL2-AS1 confers sunitinib resistance in renal cell carcinoma.Cancer Res2023;83:103-16 PMCID:PMC9811158

[46] Liu Y,Huang Z.Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma.Cell Death Dis2020;11:515 PMCID:PMC7343829

[47] Tian P,Li J,He C.An oncogenic role of lncRNA SNHG1 promotes ATG7 expression and autophagy involving tumor progression and sunitinib resistance of renal cell carcinoma.Cell Death Discov2024;10:273 PMCID:PMC11162435

[48] Pan Y,Shu G.STX17-DT facilitates axitinib resistance in renal cell carcinoma by inhibiting mitochondrial ROS accumulation and ferroptosis.Cell Death Dis2025;16:125 PMCID:PMC11847927

[49] He M,Shi H.Sunitinib increases the cancer stem cells and vasculogenic mimicry formation via modulating the lncRNA-ECVSR/ERβ/Hif2-α signaling.Cancer Lett2022;524:15-28

[50] Azijli K,Verheul HM.The potential role of lysosomal sequestration in sunitinib resistance of renal cell cancer.J Kidney Cancer VHL2015;2:195-203 PMCID:PMC5345522

[51] Li L,Liu Z.Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway.Cell Death Dis2021;12:220 PMCID:PMC7910457

[52] Chen WJ,Song X.Preoperative neoadjuvant targeted therapy remodels intra-tumoral heterogeneity of clear-cell renal cell carcinoma and ferroptosis inhibition induces resistance progression.Cancer Lett2024;593:216963

[53] Wang Q,Shou Y.AIM2 promotes renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis.Int J Biol Sci2023;19:1266-83 PMCID:PMC10008700

[54] Wu J,Liu Y,Wang X.Integrated single-cell and bulk characterization of cuproptosis key regulator PDHB and association with tumor microenvironment infiltration in clear cell renal cell carcinoma.Front Immunol2023;14:1132661 PMCID:PMC10282190

[55] Zeng X,Zhu Y.O-GlcNAcylation regulation of RIPK1-dependent apoptosis dictates sensitivity to sunitinib in renal cell carcinoma.Drug Resist Updat2024;77:101150

[56] Sato T,Maekawa M.Metabolomic analysis to elucidate mechanisms of sunitinib resistance in renal cell carcinoma.Metabolites2020;11:1 PMCID:PMC7821950

[57] Di SC,Yang W.DEPDC1 as a metabolic target regulates glycolysis in renal cell carcinoma through AKT/mTOR/HIF1α pathway.Cell Death Dis2024;15:533 PMCID:PMC11283501

[58] Amaro F,Bastos ML,Pinto J.Metabolomics reveals tyrosine kinase inhibitor resistance-associated metabolic events in human metastatic renal cancer cells.Int J Mol Sci2024;25:6328 PMCID:PMC11204329

[59] Wei Z,Ye Y.A fatty acid metabolism signature associated with clinical therapy in clear cell renal cell carcinoma.Front Genet2022;13:894736 PMCID:PMC9304894

[60] Liu J,Lin H.MTHFD2 enhances cMYC O-GlcNAcylation to promote sunitinib resistance in renal cell carcinoma.Cancer Res2025;85:1113-29

[61] Teisseire M,Parola J.De novo serine synthesis is a metabolic vulnerability that can be exploited to overcome sunitinib resistance in advanced renal cell carcinoma.Cancer Res2025;85:1857-73 PMCID:PMC12079101

[62] Longo R,Sarmiento R,Gasparini G.Integrated therapy of kidney cancer.Ann Oncol2007;18 Suppl 6:vi141-8

[63] Xuan Z,Tang W.TKI-resistant renal cancer secretes low-level exosomal miR-549a to induce vascular permeability and angiogenesis to promote tumor metastasis.Front Cell Dev Biol2021;9:689947 PMCID:PMC8222687

[64] Gu J,Han Z.Targeting the ERβ/Angiopoietin-2/Tie-2 signaling-mediated angiogenesis with the FDA-approved anti-estrogen Faslodex to increase the Sunitinib sensitivity in RCC.Cell Death Dis2020;11:367 PMCID:PMC7224303

[65] Zhao T,Wang Q.QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis.Int J Oncol2021;59:48 PMCID:PMC8208629

[66] Chen Y,Qi C.N⁶-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma.Mol Cancer2022;21:111 PMCID:PMC9087993

[67] Xiong Z,Shi J.Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress.Theranostics2020;10:11444-61 PMCID:PMC7546001

[68] Wei Z,Liu C.MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma.J Adv Res2025;70:287-305 PMCID:PMC11976417

[69] Liu J,Li S.The biology, function, and applications of exosomes in cancer.Acta Pharm Sin B2021;11:2783-97 PMCID:PMC8463268

[70] Mashouri L,Aref AR,Molaei F.Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance.Mol Cancer2019;18:75 PMCID:PMC6444571

[71] He J,Min L.Extracellular vesicles transmitted miR-31-5p promotes sorafenib resistance by targeting MLH1 in renal cell carcinoma.Int J Cancer2020;146:1052-63

[72] Lim AR,Weaver AM.Sunitinib and Axitinib increase secretion and glycolytic activity of small extracellular vesicles in renal cell carcinoma.Cancer Gene Ther2022;29:683-96 PMCID:PMC8642495

[73] Shibue T.EMT, CSCs, and drug resistance: the mechanistic link and clinical implications.Nat Rev Clin Oncol2017;14:611-29 PMCID:PMC5720366

[74] Lytle NK,Reya T.Stem cell fate in cancer growth, progression and therapy resistance.Nat Rev Cancer2018;18:669-80 PMCID:PMC8388042

[75] Guo C,Zhai W.Hypoxia increases RCC stem cell phenotype via altering the androgen receptor (AR)-lncTCFL5-2-YBX1-SOX2 signaling axis.Cell Biosci2022;12:185 PMCID:PMC9670551

[76] Lu J,Lin Z.Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer.Cancer Lett2023;564:216205

[77] Wang S,Yang DM.Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer.J Clin Invest2023;133:e160330 PMCID:PMC9843059

[78] Shrimali RK,Theoret MR,Restifo NP.Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer.Cancer Res2010;70:6171-80 PMCID:PMC2912959

[79] Puig-Kröger A,Fernández-Capetillo O.Extracellular signal-regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells.Blood2001;98:2175-82

[80] Xin H,Herrmann A,Figlin R.Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells.Cancer Res2009;69:2506-13 PMCID:PMC2664264

[81] Ozao-Choy J,Kao J.The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies.Cancer Res2009;69:2514-22 PMCID:PMC4370269

[82] Bilen MA,Voss MH.Association of neutrophil-to-lymphocyte ratio with efficacy of first-line avelumab plus axitinib vs. sunitinib in patients with advanced renal cell carcinoma enrolled in the phase 3 JAVELIN renal 101 trial.Clin Cancer Res2022;28:738-47 PMCID:PMC9377757

[83] Talmadge JE.Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy.Clin Cancer Res2007;13:5243-8

[84] Xin S,Li R.Identification of a risk model for prognostic and therapeutic prediction in renal cell carcinoma based on infiltrating M0 cells.Sci Rep2024;14:13390 PMCID:PMC11166996

[85] Aggen DH,Obradovic AZ.Blocking IL1 beta promotes tumor regression and remodeling of the myeloid compartment in a renal cell carcinoma model: multidimensional analyses.Clin Cancer Res2021;27:608-21 PMCID:PMC7980495

[86] Fumarola C,Bonelli M.Immunomodulatory effects of antiangiogenic tyrosine kinase inhibitors in renal cell carcinoma models: impact on following anti-PD-1 treatments.Biochem Pharmacol2024;226:116397

[87] Liu W,Xiong W,Zhu L.A novel FBW7/NFAT1 axis regulates cancer immunity in sunitinib-resistant renal cancer by inducing PD-L1 expression.J Exp Clin Cancer Res2022;41:38 PMCID:PMC8790872

[88] Greenberg JW,Ahn M.Combination of tipifarnib and sunitinib overcomes renal cell carcinoma resistance to tyrosine kinase inhibitors via tumor-derived exosome and T cell modulation.Cancers2022;14:903 PMCID:PMC8870174

[89] Montemagno C,Borchiellini D.Soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy in patients with metastatic clear cell renal cell carcinoma.Oncoimmunology2020;9:1846901 PMCID:PMC7714499

[90] Saito S,Yokoyama S.Targeting heat shock transcription factor 4 enhances the efficacy of cabozantinib and immune checkpoint inhibitors in renal cell carcinoma.Int J Mol Sci2025;26:1776 PMCID:PMC11855069

[91] Emanuelli A,Chouleur T.Targeting the IL34-CSF1R axis improves metastatic renal cell carcinoma therapy outcome via immune-vascular crosstalk regulation.iScience2025;28:112752 PMCID:PMC12177177

[92] Lai Y,Liang X.Connexin43 is associated with the progression of clear cell renal carcinoma and is regulated by tangeretin to sygergize with tyrosine kinase inhibitors.Transl Oncol2023;35:101712 PMCID:PMC10320623

[93] Yang Y,Zhang B.COL6A2 in clear cell renal cell carcinoma: a multifaceted driver of tumor progression, immune evasion, and drug sensitivity.J Transl Med2025;23:875 PMCID:PMC12330150

[94] Qi Y,Lin Z.Tumor-infiltrating CD39⁺CD8⁺ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients.Cancer Immunol Immunother2020;69:1565-76 PMCID:PMC11027701

[95] Murakami T,Takamatsu K.Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma.Cancer Immunol Immunother2021;70:3001-13 PMCID:PMC10992910

[96] Huinen ZR,van Beijnum JR,Griffioen AW.Anti-angiogenic agents - overcoming tumour endothelial cell anergy and improving immunotherapy outcomes.Nat Rev Clin Oncol2021;18:527-40

[97] Nowak-Sliwinska P,Griffioen CJ.Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy.Angiogenesis2023;26:279-93 PMCID:PMC10119234

[98] Chen Y,Kalluri R.Clinical and therapeutic relevance of cancer-associated fibroblasts.Nat Rev Clin Oncol2021;18:792-804 PMCID:PMC8791784

[99] Gilkes DM,Wirtz D.Hypoxia and the extracellular matrix: drivers of tumour metastasis.Nat Rev Cancer2014;14:430-9 PMCID:PMC4283800

[100] Su S,Yao H.CD10⁺GPR77⁺ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness.Cell2018;172:841-56.e16

[101] Peng YL,Zhou ZH.Single-cell transcriptomics reveals a low CD8⁺ T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma.J Immunother Cancer2022;10:e004206 PMCID:PMC8819783

[102] Errarte P,López JI.The role of cancer-associated fibroblasts in renal cell carcinoma. An example of tumor modulation through tumor/non-tumor cell interactions.J Adv Res2020;21:103-8 PMCID:PMC7015466

[103] Wang Y,Hao W.CXCL3/TGF-β-mediated crosstalk between CAFs and tumor cells augments RCC progression and sunitinib resistance.iScience2024;27:110224 PMCID:PMC11261419

[104] Chakiryan NH,Kim Y.Geospatial cellular distribution of cancer-associated fibroblasts significantly impacts clinical outcomes in metastatic clear cell renal cell carcinoma.Cancers2021;13:3743 PMCID:PMC8345222

[105] Ambrosetti D,Paoli C.Cancer-associated fibroblasts in renal cell carcinoma: implication in prognosis and resistance to anti-angiogenic therapy.BJU Int2022;129:80-92

[106] Stupichev D,Postovalova E.AI-driven multimodal algorithm predicts immunotherapy and targeted therapy outcomes in clear cell renal cell carcinoma.Cell Rep Med2025;6:102299 PMCID:PMC12432380

[107] Li Q,Chen Q.Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α.Autophagy2025;21:619-38 PMCID:PMC11849937

[108] Wang Y,Sun S.Wogonin induces apoptosis and reverses sunitinib resistance of renal cell carcinoma cells via inhibiting CDK4-RB pathway.Front Pharmacol2020;11:1152 PMCID:PMC7394056

[109] Chiang IC,Hsu YH,Yen GC.Pterostilbene and 6-shogaol exhibit inhibitory effects on sunitinib resistance and motility by suppressing the RLIP76-initiated Ras/ERK and Akt/mTOR pathways in renal cancer cells.Eur J Pharmacol2024;967:176393

[110] Kinoh H,Liu X,Cabral H.Nanomedicines blocking adaptive signals in cancer cells overcome tumor TKI resistance.J Control Release2020;321:132-44

[111] Azad AK,Vanhaesebroeck B.Inactivation of endothelial cell phosphoinositide 3-kinase β inhibits tumor angiogenesis and tumor growth.Oncogene2020;39:6480-92

[112] Rausch M,Achkhanian J,Nowak-Sliwinska P.Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma.Br J Cancer2020;123:556-67 PMCID:PMC7435198

[113] Wu Y,Yang X.Combining the tyrosine kinase inhibitor cabozantinib and the mTORC1/2 inhibitor sapanisertib blocks ERK pathway activity and suppresses tumor growth in renal cell carcinoma.Cancer Res2023;83:4161-78 PMCID:PMC10722140

[114] Kuroshima K,Okamura S.Potential new therapy of Rapalink-1, a new generation mammalian target of rapamycin inhibitor, against sunitinib-resistant renal cell carcinoma.Cancer Sci2020;111:1607-18 PMCID:PMC7226215

[115] Liu H,Shi X.Calcium saccharate/DUSP6 suppresses renal cell carcinoma glycolytic metabolism and boosts sunitinib efficacy via the ERK-AKT pathway.Biochem Pharmacol2024;224:116247

[116] Liu T,Chen X.Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma.Cell Oncol2024;47:1277-94

[117] Feng C,Tong B.Hypoxia-triggered ERRα acetylation enhanced its oncogenic role and promoted progression of renal cell carcinoma by coordinating autophagosome-lysosome fusion.Cell Death Dis2025;16:23 PMCID:PMC11739407

[118] Chen Z,Cai Y.AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments.Heliyon2024;10:e34834 PMCID:PMC11324986

[119] Kamada S,Ikeda K.Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma.Oncogene2021;40:3899-913

[120] Chen TC,Lo CY,Chang SF.Suppression of SREBP-1 expression by simvastatin decreases visfatin-induced chemoresistance to sunitinib in human renal carcinoma 786-O cells.Life2022;12:1890 PMCID:PMC9695258

[121] Khanna P,Chen CH.ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma.Sci Transl Med2021;13:eabc0170

[122] Yin L,Chen X.HOOK1 inhibits the progression of renal cell carcinoma via TGF-β and TNFSF13B/VEGF-A axis.Adv Sci2023;10:e2206955 PMCID:PMC10265082

[123] Lv M,Duan Y.Engineered biomimetic nanovesicles synergistically remodel folate-nucleotide and γ-aminobutyric acid metabolism to overcome sunitinib-resistant renal cell carcinoma.ACS Nano2024;18:27487-502

[124] Tung MC,Lee WJ.Targeting DRD2 by the antipsychotic drug, penfluridol, retards growth of renal cell carcinoma via inducing stemness inhibition and autophagy-mediated apoptosis.Cell Death Dis2022;13:400 PMCID:PMC9035181

[125] Greenberg JW,Moustafa AA.Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma.Sci Rep2021;11:10200 PMCID:PMC8119955

[126] Hua Y,Lu S.Hyaluronic acid-functionalized MOFs for combined sunitinib and siRNA therapy in renal cell carcinoma.Int J Biol Macromol2024;283:137317

[127] Oosterwijk-Wakka JC,Franssen GM.Combination of sunitinib and ¹⁷⁷Lu-labeled antibody cG250 targeted radioimmunotherapy: a promising new therapeutic strategy for patients with advanced renal cell cancer.Neoplasia2022;32:100826 PMCID:PMC9309230

[128] Oladejo M,Silwal A.Listeria-based immunotherapy directed against CD105 exerts anti-angiogenic and anti-tumor efficacy in renal cell carcinoma.Front Immunol2022;13:1038807 PMCID:PMC9692019

[129] Harvey AL,Quinn RJ.The re-emergence of natural products for drug discovery in the genomics era.Nat Rev Drug Discov2015;14:111-29

[130] Rawat L,Sasamoto Y,Pal S.A novel combination therapy with Cabozantinib and Honokiol effectively inhibits c-Met-Nrf2-induced renal tumor growth through increased oxidative stress.Redox Biol2023;68:102945 PMCID:PMC10628632

[131] Li J,Cai Y.A novel Apigenin derivative suppresses renal cell carcinoma via directly inhibiting wild-type and mutant MET.Biochem Pharmacol2021;190:114620

[132] Deeks ED.Belzutifan: first approval.Drugs2021;81:1921-7

[133] Qian K,Ren S.HDAC8 enhances the function of HIF-2α by deacetylating ETS1 to decrease the sensitivity of TKIs in ccRCC.Adv Sci2024;11:e2401142 PMCID:PMC11423204

[134] Zhang J,Lin G.Single-cell analysis reveals that vitamin C inhibits bone metastasis of renal cancer via cell cycle arrest and microenvironment remodeling.Adv Sci2025;12:e01011 PMCID:PMC12376498

[135] Paz Del Socorro T,Boulard O.The biotherapeutic Clostridium butyricum MIYAIRI 588 strain potentiates enterotropism of Rorγt⁺Treg and PD-1 blockade efficacy.Gut Microbes2024;16:2315631 PMCID:PMC10885180

[136] Barragan-Carrillo R,Saliby RM.First and second-line treatments in metastatic renal cell carcinoma.Eur Urol2025;87:143-54

[137] Chakraborty S,Sabarwal A,Pal S.Metabolic reprogramming in renal cancer: events of a metabolic disease.Biochim Biophys Acta Rev Cancer2021;1876:188559 PMCID:PMC8349779

[138] Zhang H,Wu XQ.Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor.Nat Commun2023;14:4274 PMCID:PMC10352361

[139] Meyer ML,Paz-Ares L.New promises and challenges in the treatment of advanced non-small-cell lung cancer.Lancet2024;404:803-22

[140] Zhao Y,Wang W.Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis.Lancet Oncol2024;25:1347-56

[141] Fu K,Wang F.Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance.J Hematol Oncol2022;15:173 PMCID:PMC9733018

[142] Passaro A,Mok T.Overcoming therapy resistance in EGFR-mutant lung cancer.Nat Cancer2021;2:377-91

[143] Nagase K,Rikitake-Yamamoto M.Cellular and physical microenvironments regulate the aggressiveness and sunitinib chemosensitivity of clear cell renal cell carcinoma.J Pathol2021;254:46-56 PMCID:PMC8248239

[144] Bi K,Bakouny Z.Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma.Cancer Cell2021;39:649-61.e5 PMCID:PMC8115394

[145] Quintard C,Jonsson G.A microfluidic platform integrating functional vascularized organoids-on-chip.Nat Commun2024;15:1452 PMCID:PMC10873332

[146] Zhou R,Fuchs J.Vascularised organoids: recent advances and applications in cancer research.Clin Transl Med2025;15:e70258 PMCID:PMC11882480