New advances in understanding the mechanisms and treatment challenges of ALK-targeted therapy resistance in lung cancer

Abstract

Despite the development of various effective anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), therapeutic resistance remains a major challenge. Both on-target and off-target mechanisms have been identified as key contributors to resistance. With the popularization of genetic testing and the development of precision therapies, the prognosis and survival of patients with ALK-positive non-small cell lung cancer (NSCLC) have improved. However, even with second- and third-generation ALK-TKIs, overcoming resistance remains difficult. Resistance frequently arises during approved treatments, underscoring the need for further research to elucidate the molecular events and resistance mechanisms associated with ALK-positive lung cancer. The discovery of anaplastic lymphoma kinase (ALK) rearrangement as an actionable oncogenic driver in NSCLC has established a biomarker-driven treatment paradigm for advanced disease. This article summarizes current knowledge of the mechanisms of resistance to ALK-targeted therapy in lung cancer, including both primary and acquired mechanisms, treatment strategies following resistance, recent therapeutic advances, and the impact of the immune system and tumor microenvironment. A deeper understanding of ALK-targeted therapy resistance is critical for developing new treatment strategies and may provide important insights to guide the diagnosis, treatment, and management of patients with resistant ALK⁺ lung cancer.

Keywords

Anaplastic lymphoma kinase (ALK) / drug resistance mechanisms / mutations / small cell transformation / immune microenvironment / targeted therapy

References

[1] Siegel RL,Fuchs HE.Cancer statistics, 2022.CA Cancer J Clin2022;72:7-33

[2] Shaw AT,Mino-Kenudson M.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol2009;27:4247-53 PMCID:PMC2744268

[3] McCoach CE,Gowan K.Resistance mechanisms to targeted therapies in ROS1⁺ and ALK⁺ non-small cell lung cancer.Clin Cancer Res2018;24:3334-47 PMCID:PMC6050099

[4] Pao W.New driver mutations in non-small-cell lung cancer.Lancet Oncol2011;12:175-80

[5] Soda M,Enomoto M.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.Nature2007;448:561-6

[6] Wang S,Han X.[Advances in drug resistance mechanisms and prognostic markers of targeted therapy in ALK-positive non-small cell lung cancer].Zhongguo Fei Ai Za Zhi2020;23:1014-22 PMCID:PMC7679215

[7] Shen J,Wang K.EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.Cell Signal2022;92:110264

[8] Gainor JF,Yoda S.Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.Cancer Discov2016;6:1118-33 PMCID:PMC5050111

[9] Solomon BJ,Felip E.Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the Phase III CROWN study.J Clin Oncol2024;42:3400-9 PMCID:PMC11458101

[10] Lovly CM.New benchmark for targeted therapies in lung cancer: median progression-free survival for lorlatinib in advanced ALK+ non-small cell lung cancer surpasses 5 years.J Clin Oncol2024;42:3383-6 PMCID:PMC11521153

[11] Shaw AT,Leshchiner I.Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F.N Engl J Med2016;374:54-61 PMCID:PMC4773904

[12] Toyokawa G,Shimamatsu S.Identification of a novel ALK G1123S mutation in a patient with ALK-rearranged non-small-cell lung cancer exhibiting resistance to ceritinib.J Thorac Oncol2015;10:e55-7

[13] Michels SYF,Wündisch T.ALK^G1269A mutation as a potential mechanism of acquired resistance to crizotinib in an ALK-rearranged inflammatory myofibroblastic tumor.NPJ Precis Oncol2017;1:4 PMCID:PMC5871789

[14] Okada K,Sakashita T.Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance.EBioMedicine2019;41:105-19 PMCID:PMC6441848

[15] Yanagitani N,Koike S.Drug resistance mechanisms in Japanese anaplastic lymphoma kinase-positive non-small cell lung cancer and the clinical responses based on the resistant mechanisms.Cancer Sci2020;111:932-9 PMCID:PMC7060465

[16] Lin JJ,Sequist LV.Clinical activity of alectinib in advanced RET-rearranged non-small cell lung cancer.J Thorac Oncol2016;11:2027-32

[17] Ou SH,Khan ZU.I1171 missense mutation (particularly I1171N) is a common resistance mutation in ALK-positive NSCLC patients who have progressive disease while on alectinib and is sensitive to ceritinib.Lung Cancer2015;88:231-4

[18] Ou SH,Azada MC,Ali SM.ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression.Lung Cancer2016;91:70-2

[19] Yoda S,Lawrence MS.Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer.Cancer Discov2018;8:714-29 PMCID:PMC5984716

[20] Wang Y,Xu M.Holistic view of ALK TKI resistance in ALK-positive anaplastic large cell lymphoma.Front Oncol2022;12:815654 PMCID:PMC8862178

[21] Sharma GG,Mologni L,Gambacorti-Passerini C.Tumor resistance against ALK targeted therapy-where it comes from and where it goes.Cancers2018;10:62 PMCID:PMC5876637

[22] Huang WS,Zou D.Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of anaplastic lymphoma kinase.J Med Chem2016;59:4948-64

[23] Zhang S,Squillace R.The potent ALK inhibitor brigatinib (AP26113) overcomes mechanisms of resistance to first- and second-generation ALK inhibitors in preclinical models.Clin Cancer Res2016;22:5527-38

[24] Gainor JF,Logan J.Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer relapsing on standard dose alectinib.J Thorac Oncol2016;11:256-60 PMCID:PMC4743545

[25] Redaelli S,Zappa M.Lorlatinib treatment elicits multiple on- and off-target mechanisms of resistance in ALK-driven cancer.Cancer Res2018;78:6866-80

[26] Zou HY,Kodack DP.PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models.Cancer Cell2015;28:70-81 PMCID:PMC4504786

[27] Lin JJ,Shaw AT.Targeting ALK: precision medicine takes on drug resistance.Cancer Discov2017;7:137-55 PMCID:PMC5296241

[28] Peters S.Management of resistance to first-line anaplastic lymphoma kinase tyrosine kinase inhibitor therapy.Curr Treat Options Oncol2018;19:37

[29] Cooper AJ,Lin JJ.Author Correction: Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management.Nat Rev Clin Oncol2022;19:744

[30] Sampson J,Zhang N,Choi J.Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.Cell Death Dis2024;15:912 PMCID:PMC11655848

[31] Bauman JR,Preeshagul I.Real-world treatment sequencing and effectiveness of second- and third-generation ALK tyrosine kinase inhibitors for ALK-positive advanced non-small cell lung cancer.Lung Cancer2024;195:107919

[32] Liu L,Liu Y,Zhang H.A case of lung adenocarcinoma response to alectinib harboring a rare EML4-ALK variant, Exon 6 of EML4 fused to Exon 18 of ALK.J Natl Compr Canc Netw2021;20:2-6

[33] Li X,Chen C.A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance.iScience2024;27:109015 PMCID:PMC10847737

[34] Gainor JF.Novel targets in non-small cell lung cancer: ROS1 and RET fusions.Oncologist2013;18:865-75 PMCID:PMC3720641

[35] Nam Y,Kim N,Selim KB.Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors.J Enzyme Inhib Med Chem2019;34:1426-38 PMCID:PMC6713165

[36] Wang KL,Hsu PC.Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.J Enzyme Inhib Med Chem2024;39:2318645 PMCID:PMC10930102

[37] Gerlinger M,Swanton C.Acquired resistance to crizotinib from a mutation in CD74-ROS1.N Engl J Med2013;369:1172-3

[38] Yang Y,Gao Y.EML4-ALK G1202R and EML4-ALK L1196M mutations induce crizotinib resistance in non-small cell lung cancer cells through activating epithelial-mesenchymal transition mediated by MDM2/MEK/ERK signal axis.Cell Biol Int2025;49:55-67

[39] Leporati R,Beninato T.Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs.Tumori2024;110:NP1-4

[40] Friboulet L,Katayama R.The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.Cancer Discov2014;4:662-73 PMCID:PMC4068971

[41] Katayama R,Khan TM.Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers.Sci Transl Med2012;4:120ra17 PMCID:PMC3385512

[42] Li Y,Ma Y.Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory.Transl Lung Cancer Res2024;13:152-62 PMCID:PMC10891411

[43] Han R,Hu C.Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.Acta Pharmacol Sin2024;45:1264-75 PMCID:PMC11130302

[44] Chapman AM,Ruestow P,Madl AK.Lung cancer mutation profile of EGFR, ALK, and KRAS: meta-analysis and comparison of never and ever smokers.Lung Cancer2016;102:122-34

[45] Yamada T,Nakade J.Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells.Clin Cancer Res2012;18:3592-602

[46] Ruiz CF,Haley JA,Haley JD.SREBP1 regulates mitochondrial metabolism in oncogenic KRAS expressing NSCLC.FASEB J2020;34:10574-89 PMCID:PMC8335704

[47] Ma X,Qi X.Identification of a novel Src inhibitor K882 derived from quinazoline-based stilbenes with anti-NSCLC effect.Bioorg Chem2025;156:108185

[48] Janostiak R,Wajapeyee N.Anaplastic lymphoma kinase confers resistance to BRAF kinase inhibitors in melanoma.iScience2019;16:453-67 PMCID:PMC6593146

[49] Dong X,Li E.Elucidation of resistance mechanisms to second-generation ALK inhibitors alectinib and ceritinib in non-small cell lung cancer cells.Neoplasia2016;18:162-71 PMCID:PMC4796802

[50] Urbanska EM,Melchior LC,Santoni-Rugiu E.Changing ALK-TKI-resistance mechanisms in rebiopsies of ALK-rearranged NSCLC: ALK- and BRAF-mutations followed by epithelial-mesenchymal transition.Int J Mol Sci2020;21:2847 PMCID:PMC7215933

[51] Zhuang X,Li J.Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF.Cancer Med2019;8:2858-66 PMCID:PMC6558647

[52] Talwelkar SS,Schüler J.PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer.Mol Oncol2023;17:747-64 PMCID:PMC10158778

[53] Hao XL,Deng XJ.Identification of TC2N as a novel promising suppressor of PI3K-AKT signaling in breast cancer.Cell Death Dis2019;10:424 PMCID:PMC6541591

[54] Smiles WJ,Stefan VE,Kofler B.Metabolic protein kinase signalling in neuroblastoma.Mol Metab2023;75:101771 PMCID:PMC10362370

[55] Xie J,Xu W.Mechanisms of resistance to ALK inhibitors and corresponding treatment strategies in lung cancer.Int J Gen Med2025;18:2151-71 PMCID:PMC12010037

[56] Li Y,Zhang H.EML4-ALK-mediated activation of the JAK2-STAT pathway is critical for non-small cell lung cancer transformation.BMC Pulm Med2021;21:190 PMCID:PMC8180148

[57] Govindan R,Griffith M.Genomic landscape of non-small cell lung cancer in smokers and never-smokers.Cell2012;150:1121-34 PMCID:PMC3656590

[58] Conlon TM,Heide D.Inhibition of LTβR signalling activates WNT-induced regeneration in lung.Nature2021;588:151-6 PMCID:PMC7718297

[59] Lin Y,Shintani T.Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells.Sci Rep2020;10:4748 PMCID:PMC7076038

[60] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2020;68:394-424

[61] Clamon G,An J.Transformational changes between non-small cell and small cell lung cancer-biological and clinical relevance - a review.Am J Clin Oncol2020;43:670-5

[62] Yin X,Wang H.Small cell lung cancer transformation: from pathogenesis to treatment.Semin Cancer Biol2022;86:595-606

[63] Socinski MA,Halle JS.Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.J Clin Oncol2004;22:4341-50

[64] Oser MG,Sequist LV.Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin.Lancet Oncol2015;16:e165-72 PMCID:PMC4470698

[65] Fujita S,Katakami N.Transformation to SCLC after treatment with the ALK inhibitor alectinib.J Thorac Oncol2016;11:e67-72

[66] Miyamoto S,Ono R.Transformation to small-cell lung cancer as a mechanism of acquired resistance to crizotinib and alectinib.Jpn J Clin Oncol2016;46:170-3

[67] Roca E,Amoroso V,Ferrari V.Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: a systematic review and pooled analysis.Cancer Treat Rev2017;59:117-22

[68] Marcoux N,O’Kane G.EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes.J Clin Oncol2019;37:278-85 PMCID:PMC7001776

[69] Imakita T,Kanai O.Small cell transformation of non-small cell lung cancer under immunotherapy: case series and literature review.Thorac Cancer2021;12:3062-7 PMCID:PMC8590890

[70] Levacq D,de Wind R,Berghmans T.Histological transformation of ALK rearranged adenocarcinoma into small cell lung cancer: a new mechanism of resistance to ALK inhibitors.Lung Cancer2016;102:38-41

[71] Hobeika C,Eid R.ALK-rearranged adenocarcinoma transformed to small-cell lung cancer: a new entity with specific prognosis and treatment?.Per Med2018;15:111-5

[72] Zhou N,William WN Jr.Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer.J Immunother Cancer2024;12:e009677 PMCID:PMC11499765

[73] Zhang D,Liu G.Novel FABP4⁺C1q⁺ macrophages enhance antitumor immunity and associated with response to neoadjuvant pembrolizumab and chemotherapy in NSCLC via AMPK/JAK/STAT axis.Cell Death Dis2024;15:717 PMCID:PMC11445384

[74] Lu C,Wu D.Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect.J Immunother Cancer2024;12:e009165 PMCID:PMC11328648

[75] Zhang B,Zhang H.Characteristics of the immune microenvironment and their clinical significance in non-small cell lung cancer patients with ALK-rearranged mutation.Front Immunol2022;13:974581 PMCID:PMC9494286

[76] Gainor JF,Sequist LV.EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.Clin Cancer Res2016;22:4585-93 PMCID:PMC5026567

[77] Budczies J,Kluck K.Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma.Cancer Immunol Immunother2022;71:251-65 PMCID:PMC8783861

[78] Liu SY,Wu SP.Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer.Lung Cancer2018;125:86-92

[79] Horvat NK,Marques O.Superparamagnetic iron oxide nanoparticles reprogram the tumor microenvironment and reduce lung cancer regrowth after crizotinib treatment.ACS Nano2024;18:11025-41 PMCID:PMC11064219

[80] Camidge DR,Kerr KM.Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC.Nat Rev Clin Oncol2019;16:341-55

[81] Gu D,Huang S.Expression and clinical significance of programmed death ligand-1 evaluated by 22C3 antibody in pleural effusion metastatic non-small-cell lung cancer.Cytojournal2024;21:70 PMCID:PMC11801688

[82] Peng S,Zhang X.EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression.Mol Cancer2019;18:165 PMCID:PMC6864970

[83] Qi R,Shen M,He S.Current status and challenges of immunotherapy in ALK rearranged NSCLC.Front Oncol2022;12:1016869 PMCID:PMC9795041

[84] Zhang Q,Chen Y,Zhang X.A novel mTORC1/2 inhibitor (MTI-31) inhibits tumor growth, epithelial-mesenchymal transition, metastases, and improves antitumor immunity in preclinical models of lung cancer.Clin Cancer Res2019;25:3630-42

[85] Spigel DR,Waterhouse D.Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (CheckMate 370).J Thorac Oncol2018;13:682-8

[86] Golding B,Jones R.The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC).Mol Cancer2018;17:52 PMCID:PMC5817728

[87] Furugaki K,Sakaguchi N.Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.Mol Oncol2025;19:519-39 PMCID:PMC11793004

[88] Hong S,Fang W.Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients.Oncoimmunology2016;5:e1094598 PMCID:PMC4839382

[89] Ota K,Kawahara A.Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer.Clin Cancer Res2015;21:4014-21

[90] Du P,An Z,Liu L.In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand-1 inhibitor in anaplastic lymphoma kinase-rearranged non-small-cell lung cancer.Cancer Sci2020;111:1887-98 PMCID:PMC7293083

[91] Felip E,Maur M.Ceritinib plus nivolumab in patients with advanced ALK-rearranged non-small cell lung cancer: results of an open-label, multicenter, phase 1B study.J Thorac Oncol2020;15:392-403

[92] Gan GN,Scheier B.Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib.Int J Radiat Oncol Biol Phys2014;88:892-8 PMCID:PMC4160890

[93] Chen Y,Su C.Apatinib reverses alectinib resistance by targeting vascular endothelial growth factor receptor 2 and attenuating the oncogenic signaling pathway in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene-positive lung cancer cell lines.Anticancer Drugs2018;29:935-43

[94] Choudhury NJ,Sellitti M,Drilon A.Lorlatinib and bevacizumab activity in ALK-rearranged lung cancers after lorlatinib progression.JCO Precis Oncol2020;4:PO.20.00271 PMCID:PMC7713518

[95] Choi SH,Choi YJ.Multiple receptor tyrosine kinase activation related to ALK inhibitor resistance in lung cancer cells with ALK rearrangement.Oncotarget2017;8:58771-80 PMCID:PMC5601691

[96] Miyawaki M,Tani T.Overcoming EGFR bypass signal-induced acquired resistance to ALK tyrosine kinase inhibitors in ALK-translocated lung cancer.Mol Cancer Res2017;15:106-14

[97] Tani T,Hamamoto J.Activation of EGFR bypass signaling by TGFα overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells.Mol Cancer Ther2016;15:162-71

[98] Kang J,Zhang XC.Heterogeneous responses and resistant mechanisms to crizotinib in ALK-positive advanced non-small cell lung cancer.Thorac Cancer2018;9:1093-103 PMCID:PMC6119621

[99] Hrustanovic G,Pazarentzos E.RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.Nat Med2015;21:1038-47 PMCID:PMC4734742

[100] Zhou B.Up-front polytherapy for ALK-positive lung cancer.Nat Med2015;21:974-5

[101] Shrestha N,Bower RL,Ashton JC.Inhibition of mitogen-activated protein kinase kinase alone and in combination with anaplastic lymphoma kinase (ALK) inhibition suppresses tumor growth in a mouse model of ALK-positive lung cancer.J Pharmacol Exp Ther2020;374:134-40

[102] Shrestha N,Dass P,Ashton JC.Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer.Sci Rep2019;9:18842 PMCID:PMC6906283

[103] Tanizaki J,Takezawa K.Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells.Br J Cancer2012;106:763-7 PMCID:PMC3322944

[104] Jänne PA,Camidge DR.Combined Pan-HER and ALK/ROS1/MET inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer: results of a phase I study.J Thorac Oncol2016;11:737-47

[105] Liu QG,Wang ZY.ALK-based dual inhibitors: focus on recent development for non-small cell lung cancer therapy.Eur J Med Chem2025;291:117646

[106] Jiang C,Jia K,Ren X.Exploring cellular plasticity and resistance mechanisms in lung cancer: Innovations and emerging therapies.J Pharm Anal2025;15:101179 PMCID:PMC12151197

[107] Yamaguchi N,Nakayama S.Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer.Lung Cancer2014;83:37-43 PMCID:PMC3947244

[108] Rossing HH,Urbanska EM.Concomitant occurrence of EGFR (epidermal growth factor receptor) and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations in an ALK (anaplastic lymphoma kinase)-positive lung adenocarcinoma patient with acquired resistance to crizotinib: a case report.BMC Res Notes2013;6:489 PMCID:PMC3879082

[109] Sahnane N,Bernasconi B.EGFR and KRAS mutations in ALK-positive lung adenocarcinomas: biological and clinical effect.Clin Lung Cancer2016;17:56-61

[110] Sweis RF,Bank B,Mooney C.Concurrent EGFR mutation and ALK translocation in non-small cell lung cancer.Cureus2016;8:e513 PMCID:PMC4807912

[111] Yang JJ,Su J.Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation.Clin Cancer Res2014;20:1383-92

[112] Drilon A,Lai GGY.Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.Nat Rev Clin Oncol2018;15:150

[113] Lehman A,Aitken S.Cytomegalovirus viremia and hepatitis B reactivation in patient with RET fusion-positive non-small cell lung cancer treated with pralsetinib.J Oncol Pharm Pract2025;31:674-8

[114] Zheng Q,Huang Y,Zhang L.Identification of a novel KIF5B-RET, ABHD17C-RET double-fusion variant in lung adenocarcinoma and response to cabozantinib.J Thorac Oncol2020;15:e132-3

[115] Song Z,Ji Y.An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core.Eur J Med Chem2016;118:244-9

[116] Chen JF,He B.Advances of dual inhibitors based on ALK for the treatment of cancer.Bioorg Chem2025;159:108417

[117] Kohno T,Totoki Y.KIF5B-RET fusions in lung adenocarcinoma.Nat Med2012;18:375-7 PMCID:PMC6430196

[118] Parvaresh H,Golandam F,Jabbarzadeh Kaboli P.Unraveling the potential of ALK-targeted therapies in non-small cell lung cancer: comprehensive insights and future directions.Biomedicines2024;12:297 PMCID:PMC10887432

[119] Li MSC,Mok TSK.Developments in targeted therapy & immunotherapy-how non-small cell lung cancer management will change in the next decade: a narrative review.Ann Transl Med2023;11:358 PMCID:PMC10477626

[120] Hu Z,Zhang Y.PD-L1 mRNA derived from tumor-educated platelets as a potential immunotherapy biomarker in non-small cell lung cancer.Transl Lung Cancer Res2024;13:345-54 PMCID:PMC10938106

[121] Cavazzoni A,Volta F.PD-L1 overexpression induces STAT signaling and promotes the secretion of pro-angiogenic cytokines in non-small cell lung cancer (NSCLC).Lung Cancer2024;187:107438

[122] Reck M, Mok TSK, Nishio M, et al; IMpower150 Study Group. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7:387-401.

[123] Gaissmaier L.Immune modulation in lung cancer: current concepts and future strategies.Respiration2021;99:903-29

[124] Wang Q,Zhou C.Recent advances in immunotherapy for lung cancer.Cancer Innov2023;2:18-24 PMCID:PMC10686166

[125] Furugaki K,Mizuta H.FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes.NPJ Precis Oncol2023;7:107 PMCID:PMC10600219

[126] Haderk F,Cech L.Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.Nat Commun2024;15:3741 PMCID:PMC11068778

[127] Huang S,Armstrong EA.Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation.Cancer Res2013;73:824-33 PMCID:PMC7254871

[128] Hao Y,Huang D.Developing a semi-supervised approach using a PU-learning-based data augmentation strategy for multitarget drug discovery.Int J Mol Sci2024;25:8239 PMCID:PMC11312053

[129] Xu L,Xu C.Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET.Cancer Res2012;72:3302-11 PMCID:PMC3389159

[130] Iacono D,Metro G.Future options for ALK-positive non-small cell lung cancer.Lung Cancer2015;87:211-9

[131] Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41-50.

[132] Jeon H,Song J,Cheng H.Update 2025: management of non‑small-cell lung cancer.Lung2025;203:53 PMCID:PMC11937135

[133] Voena C,Iannelli F.ALK in cancer: from function to therapeutic targeting.Nat Rev Cancer2025;25:359-78 PMCID:PMC12208075

[134] Keam SJ.Iruplinalkib: first approval.Drugs2023;83:1717-21

[135] Yang Y,Yang N.Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial.Signal Transduct Target Ther2023;8:301 PMCID:PMC10423717

[136] Recondo G,Facchinetti F.Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer.Clin Cancer Res2020;26:242-55 PMCID:PMC6942925

[137] Wang J,Zheng Q,Chen J.Newly emerged ROS1 rearrangement in a patient with lung adenocarcinoma following resistance to immune checkpoint inhibitors: a case report.Front Oncol2024;14:1507658 PMCID:PMC11668661

[138] Liao Y,Li X.Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2.Cell Chem Biol2024;31:284-97.e10 PMCID:PMC10922442

[139] Murray BW,Deng W.TPX-0131, a potent CNS-penetrant, next-generation inhibitor of wild-type ALK and ALK-resistant mutations.Mol Cancer Ther2021;20:1499-507 PMCID:PMC9398166

[140] Ou SI,Brazel D,Zhu VW.Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?.Transl Oncol2021;14:101191 PMCID:PMC8353359

[141] Lin JJ,Tangpeerachaikul A.NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK-mutant oncoproteins, including lorlatinib-resistant compound mutations.Cancer Discov2024;14:2367-86 PMCID:PMC11609626

[142] Pulte ED,Wang Y.FDA Approval Summary: gilteritinib for relapsed or refractory acute myeloid leukemia with a FLT3 mutation.Clin Cancer Res2021;27:3515-21 PMCID:PMC8506653

[143] Nishio M,Wu YL.Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer.Cancer Res Treat2018;50:691-700 PMCID:PMC6056984

[144] Yang Q,Gao T.SIRT1 silencing promotes EMT and crizotinib resistance by regulating autophagy through AMPK/mTOR/S6K signaling pathway in EML4-ALK L1196M and EML4-ALK G1202R mutant non-small cell lung cancer cells.Mol Carcinog2024;63:2133-44

[145] Reck M,Robinson AG.Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater.J Clin Oncol2019;37:537-46 PMCID:PMC6688776