ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies

Abstract

Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.

Keywords

NSCLC / ALK TKI / acquired resistance / alectinib / crizotinib / lorlatinib / ceritinib / brigatinib

References

[1] Barlesi F,Merlio JP.Biomarkers France contributorsRoutine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).Lancet2016;387:1415-26

[2] Kris MG,Berry LD.Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.JAMA2014;311:1998-2006 PMCID:PMC4163053

[3] Morris SW,Valentine MB.Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma.Science1994;263:1281-4

[4] Wellstein A.ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers.Front Oncol2012;2:192 PMCID:PMC3525999

[5] Du Z.Mechanisms of receptor tyrosine kinase activation in cancer.Mol Cancer2018;17:58 PMCID:PMC5817791

[6] Hallberg B.Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology.Nat Rev Cancer2013;13:685-700

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

[8] Schneider JL,Shaw AT.ALK-positive lung cancer: a moving target.Nat Cancer2023;4:330-43 PMCID:PMC10754274

[9] Shaw AT,Nakagawa K.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.N Engl J Med2013;368:2385-94

[10] Chia PL,Dobrovic A.Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors.Clin Epidemiol2014;6:423-32 PMCID:PMC4242069

[11] Caliò A,Gilioli E.ALK/EML4 fusion gene may be found in pure squamous carcinoma of the lung.J Thorac Oncol2014;9:729-32

[12] Yin K,Li LL.Low frequency of mutation of epidermal growth factor receptor (EGFR) and arrangement of anaplastic lymphoma kinase (ALK) in primary pulmonary lymphoepithelioma-like carcinoma.Thorac Cancer2020;11:346-52 PMCID:PMC6997003

[13] Solomon BJ, Mok T, Kim DW, et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer.N Engl J Med2014;371:2167-77

[14] Camidge DR,Kwak EL.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol2012;13:1011-9 PMCID:PMC3936578

[15] Kim D,Yang P.Updated results of a global phase II study with crizotinib in advanced alk-positive non-small cell lung cancer (NSCLC).Ann Oncol2012;23:ix402

[16] Wu YL,Lu Y.Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer.J Thorac Oncol2018;13:1539-48

[17] Kim DW,Tan DSW.Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial.Lancet Oncol2016;17:452-63 PMCID:PMC5063047

[18] Crinò L,De Marinis F.Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2.J Clin Oncol2016;34:2866-73

[19] Felip E,Park K.ASCEND-3: A single-arm, open-label, multicenter phase II study of ceritinib in ALKi-naïve adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC).J Clin Oncol2015;33:8060

[20] Soria JC,Chiari R.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.Lancet2017;389:917-29

[21] Shaw AT,Crinò L.Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol2017;18:874-86

[22] Zhang L,Tan D.445PD ASCEND-6: single-arm, open label, multicenter phase 1/2 study of ceritinib in Chinese pts with advanced ALK- rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with crizotinib.Ann Oncol2016;27:ix143

[23] Cho BC,Bearz A.ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC).J Thorac Oncol2017;12:1357-67

[24] Seto T,Nishio M.CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.Lancet Oncol2013;14:590-8

[25] Gandhi L, Shaw A, Gadgeel SM, et al; NP28761 Study Investigators. A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761).J Clin Oncol2015;33:8019

[26] Ou SI,De Petris L.Efficacy and safety of the ALK inhibitor alectinib in ALK + non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673).J Clin Oncol2015;33:8008

[27] Peters S, Camidge DR, Shaw AT, et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.N Engl J Med2017;377:829-38

[28] Novello S,Oh IJ.Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.Ann Oncol2018;29:1409-16 PMCID:PMC6005013

[29] Hida T,Kondo M.Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.Lancet2017;390:29-39

[30] Zhou C,Reungwetwattana T.Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study.Lancet Respir Med2019;7:437-46

[31] Hochmair M,Reckamp K.Brigatinib in crizotinib-refractory ALK+ NSCLC: updates from the pivotal randomized phase 2 Trial (ALTA).Ann Oncol2017;28:ii35-6

[32] Camidge DR,Ahn MJ.Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer.N Engl J Med2018;379:2027-39

[33] Yoshida T,Toyozawa R.Brigatinib in Japanese patients with ALK-positive non-small-cell lung cancer: final results of the phase 2 J-ALTA trial.Cancer Sci2023;114:3698-707 PMCID:PMC10475780

[34] Kim ES,Mok T.ALTA-2: phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib.Future Oncol2021;17:1709-19

[35] Yang JC,Lu S.Brigatinib versus alectinib in ALK-positive NSCLC after disease progression on crizotinib: results of phase 3 ALTA-3 trial.J Thorac Oncol2023;18:1743-55

[36] Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.N Engl J Med2020;383:2018-29

[37] BioRender (2020). Available from: https://app.biorender.com. [Last accessed on 17 May 2024]

[38] National Center for Biotechnology Information. PubChem compound summary for CID 11626560, Crizotinib. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Crizotinib. [Last accessed on 17 May 2024]

[39] National Center for Biotechnology Information. PubChem compound summary for CID 68165256, Brigatinib. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Brigatinib. [Last accessed on 17 May 2024]

[40] National Center for Biotechnology Information. PubChem compound summary for CID 49806720, Alectinib. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Alectinib. [Last accessed on 17 May 2024]

[41] National Center for Biotechnology Information. PubChem compound summary for CID 71731823, Lorlatinib. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Lorlatinib. [Last accessed on 17 May 2024]

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

[43] Lin JJ.Resisting resistance: targeted therapies in lung cancer.Trends Cancer2016;2:350-64 PMCID:PMC5091655

[44] 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

[45] Toyokawa G,Inamasu E.Secondary mutations at I1171 in the ALK gene confer resistance to both Crizotinib and Alectinib.J Thorac Oncol2014;9:e86-7

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

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

[48] Ignatius Ou SH,Hsiang DJ.Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib.J Thorac Oncol2014;9:549-53

[49] Katayama R,Benes C.Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.Proc Natl Acad Sci U S A2011;108:7535-40 PMCID:PMC3088626

[50] Cuyàs E,Micol V,Bosch-Barrera J.STAT3-targeted treatment with silibinin overcomes the acquired resistance to crizotinib in ALK-rearranged lung cancer.Cell Cycle2016;15:3413-8 PMCID:PMC5224449

[51] Chen H,Zhang Y,Zhang B.Afatinib reverses ceritinib resistance (CR) in ALK/ROS1-positive non-small-cell lung cancer cell (NSCLC) via suppression of NRG1 pathway.Onco Targets Ther2018;11:8201-9 PMCID:PMC6267764

[52] Song X,Qu X,Jiang B.Two novel strategies to overcome the resistance to ALK tyrosine kinase inhibitor drugs: macrocyclic inhibitors and proteolysis-targeting chimeras.MedComm2021;2:341-50 PMCID:PMC8554663

[53] Mizuta H,Araki M.Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer.Nat Commun2021;12:1261 PMCID:PMC7904790

[54] Choi YL, Soda M, Yamashita Y, et al; ALK Lung Cancer Study Group. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.N Engl J Med2010;363:1734-9

[55] Sasaki T,Ogino A.A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.Cancer Res2011;71:6051-60 PMCID:PMC3278914

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

[57] Doebele RC,Aisner DL.Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.Clin Cancer Res2012;18:1472-82 PMCID:PMC3311875

[58] 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

[59] Shiba-Ishii A,Dagogo-Jack I.Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer.Nat Cancer2022;3:710-22 PMCID:PMC9732888

[60] Tanizaki J,Okabe T.Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer.Clin Cancer Res2012;18:6219-26

[61] 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

[62] Engelman JA,Mitsudomi T.MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Science2007;316:1039-43

[63] Matsumoto K,De Silva DM,Bottaro DP.Hepatocyte growth factor/MET in cancer progression and biomarker discovery.Cancer Sci2017;108:296-307 PMCID:PMC5378267

[64] Dagogo-Jack I,Lennerz JK.MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer.Clin Cancer Res2020;26:2535-45 PMCID:PMC7269872

[65] Dardaei L,Singh M.SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors.Nat Med2018;24:512-7 PMCID:PMC6343825

[66] Chen H,Peng T.Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1.Cell Death Dis2020;11:111 PMCID:PMC7010683

[67] Yang H,Deng Q.Predictive and prognostic value of phosphorylated c-KIT and PDGFRA in advanced non-small cell lung cancer harboring ALK fusion.Oncol Lett2019;17:3071-6 PMCID:PMC6396115

[68] Lovly CM,Chen H.Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.Nat Med2014;20:1027-34 PMCID:PMC4159407

[69] Wilson C,Nehoff H.ALK and IGF-1R as independent targets in crizotinib resistant lung cancer.Sci Rep2017;7:13955 PMCID:PMC5654778

[70] Shi R,Li M.BRAF V600E mutation and MET amplification as resistance pathways of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in lung cancer.Lung Cancer2020;146:78-85

[71] Tsuji T,Aoki W.YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation.Nat Commun2020;11:74 PMCID:PMC6941996

[72] Yu Y,Wu X.Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer.Lung Cancer2019;127:19-24

[73] Roche J.The epithelial-to-mesenchymal transition in cancer.Cancers2018;10:52 PMCID:PMC5836084

[74] Gower A,Hsu ST,Giaccone G.EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer.Mol Oncol2016;10:601-9 PMCID:PMC5423150

[75] 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

[76] Takegawa N,Iizuka N.Transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer in association with acquired resistance to alectinib.Ann Oncol2016;27:953-5

[77] 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

[78] Niederst MJ,Poirier JT.RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.Nat Commun2015;6:6377 PMCID:PMC4357281

[79] Koyama K,Jimbo N.Overexpression of CD 133 and BCL-2 in non-small cell lung cancer with neuroendocrine differentiation after transformation in ALK rearrangement-positive adenocarcinoma.Pathol Int2019;69:294-9

[80] Katayama R,Yanagitani N.P-glycoprotein mediates ceritinib resistance in anaplastic lymphoma kinase-rearranged non-small cell lung cancer.EBioMedicine2016;3:54-66 PMCID:PMC4739423

[81] Kort A,Wagenaar E,Schinkel AH.Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2).Pharmacol Res2015;102:200-7

[82] Kodama T,Takanashi K,Kondoh O.Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.Cancer Chemother Pharmacol2014;74:1023-8

[83] Kim S,Kim DW.Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer.J Thorac Oncol2013;8:415-22

[84] 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

[85] Dehghanian F,Vallian S.F1174V mutation alters the ALK active conformation in response to Crizotinib in NSCLC: insight from molecular simulations.J Mol Graph Model2017;75:287-93

[86] Ai X,Chang L,Ou SI.Next generation sequencing reveals a novel ALK G1128A mutation resistant to crizotinib in an ALK-Rearranged NSCLC patient.Lung Cancer2018;123:83-6

[87] Horn L,Wu G.Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial.JAMA Oncol2021;7:1617-25 PMCID:PMC8414368

[88] Horn L,Reckamp KL.Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II, multicenter study.Clin Cancer Res2018;24:2771-9 PMCID:PMC6004248

[89] Lovly CM,Gainor JF.Managing resistance to EFGR- and ALK-targeted therapies.Am Soc Clin Oncol Educ Book2017;37:607-18 PMCID:PMC10183098

[90] Sasaki T,Zheng W.The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.Cancer Res2010;70:10038-43 PMCID:PMC3045808

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

[92] Guan J,Siaw JT.Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.Cold Spring Harb Mol Case Stud2018;4:a002550 PMCID:PMC6071567

[93] 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. [PMID: 25736571 DOIi 10.1016/j.lungcan.2015]

[94] Katayama R,Koike S.Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.Clin Cancer Res2014;20:5686-96 PMCID:PMC4233168

[95] Lin YT,Hung JY.Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.Eur J Cancer2021;156:1-11

[96] 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

[97] Sabari JK,Schram AM.The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers.Onco Targets Ther2017;10:1983-92 PMCID:PMC5388194

[98] 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

[99] Johnson TW,Bailey S.Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.J Med Chem2014;57:4720-44

[100] Camidge DR.Lorlatinib should not be considered as the preferred first-line option in patients with advanced ALK rearranged NSCLC.J Thorac Oncol2021;16:528-31

[101] Bauer TM,Johnson ML.Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer.Target Oncol2020;15:55-65 PMCID:PMC7028836

[102] Nishino M,Mitsudomi T.Brain metastases in oncogene-driven non-small cell lung cancer.Transl Lung Cancer Res2019;8:S298-307 PMCID:PMC6894990

[103] Solomon BJ,Bauer TM.Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.Lancet Oncol2018;19:1654-67

[104] Dagogo-Jack I,Lin JJ.Treatment with next-generation ALK inhibitors fuels plasma ALK mutation diversity.Clin Cancer Res2019;25:6662-70 PMCID:PMC6858956

[105] Pailler E,Oulhen M.Acquired resistance mutations to ALK inhibitors identified by single circulating tumor cell sequencing in ALK-rearranged non-small-cell lung cancer.Clin Cancer Res2019;25:6671-82

[106] Zhu VW,Madison R,Cui J.A novel sequentially evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis confers resistance to lorlatinib: a brief report and literature review.JTO Clin Res Rep2021;2:100116 PMCID:PMC8474455

[107] Zhang L,Li X.Clinical features of Bim deletion polymorphism and its relation with crizotinib primary resistance in Chinese patients with ALK/ROS1 fusion-positive non-small cell lung cancer.Cancer2017;123:2927-35

[108] Rihawi K,Fiorentino M.MYC amplification as a potential mechanism of primary resistance to crizotinib in ALK-rearranged non-small cell lung cancer: a brief report.Transl Oncol2019;12:116-21 PMCID:PMC6171095

[109] Heuckmann JM,Malchers F.Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.Clin Cancer Res2012;18:4682-90

[110] Yoshida T,Tanaka K.Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer.J Clin Oncol2016;34:3383-9

[111] Tabbò F,Bironzo P.Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won.Transl Lung Cancer Res2020;9:2545-56 PMCID:PMC7815358

[112] Su KY,Li KC.Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer.J Clin Oncol2012;30:433-40

[113] Lucena-Araujo AR,VanderLaan PA.De novo ALK kinase domain mutations are uncommon in kinase inhibitor-naïve ALK rearranged lung cancers.Lung Cancer2016;99:17-22 PMCID:PMC5002311

[114] Mazieres J,Lusque A.Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.Ann Oncol2019;30:1321-8 PMCID:PMC7389252

[115] Jahanzeb M,Pan X,Baumann P.Immunotherapy treatment patterns and outcomes among ALK-positive patients with non-small-cell lung cancer.Clin Lung Cancer2021;22:49-57

[116] 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

[117] 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

[118] Patel M,Malhotra J.ALK inhibitors and checkpoint blockade: a cautionary tale of mixing oil with water?.J Thorac Dis2018;10:S2198-201 PMCID:PMC6072958

[119] 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

[120] Desai A.Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review.Transl Lung Cancer Res2023;12:615-28 PMCID:PMC10087990

[121] Dagogo-Jack I,Heist RS.Efficacy and tolerability of ALK/MET combinations in patients with ALK-rearranged lung cancer with acquired met amplification: a retrospective analysis.JTO Clin Res Rep2023;4:100534 PMCID:PMC10391652

[122] Coleman N,Heymach JV,Le X.Antibody-drug conjugates in lung cancer: dawn of a new era?.NPJ Precis Oncol2023;7:5 PMCID:PMC9834242

[123] Camidge DR,Horinouchi H.Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met-overexpressing (OE) advanced non-small cell lung cancer (NSCLC).J Clin Oncol2022;40:9016

[124] Levy BP,Reck M.TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC.Future Oncol2023;19:1461-72

[125] Schneider M,Hercules A.The PROTACtable genome.Nat Rev Drug Discov2021;20:789-97

[126] Li JW,Kaye FJ.PROTAC therapy as a new targeted therapy for lung cancer.Mol Ther2023;31:647-56 PMCID:PMC10014230

[127] Powell CE,Tan L.Chemically induced degradation of anaplastic lymphoma kinase (ALK).J Med Chem2018;61:4249-55 PMCID:PMC6294449

[128] Zhang C,Yang X.Proteolysis targeting chimeras (PROTACs) of anaplastic lymphoma kinase (ALK).Eur J Med Chem2018;151:304-14 PMCID:PMC5924614

[129] Liu J,Ma L.Light-induced control of protein destruction by opto-PROTAC.Sci Adv2020;6:eaay5154 PMCID:PMC7034987

[130] Ren C,Kong Y.Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib.Eur J Med Chem2021;217:113335

[131] Sun N,Kong Y.Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.Eur J Med Chem2020;193:112190

[132] Kang CH,Lee CO,Park CH.Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC).Biochem Biophys Res Commun2018;505:542-7

[133] Xie S,Liu Y.Development of alectinib-based PROTACs as novel potent degraders of anaplastic lymphoma kinase (ALK).J Med Chem2021;64:9120-40

[134] Yan G,Yue L.Discovery of a PROTAC targeting ALK with in vivo activity.Eur J Med Chem2021;212:113150

[135] Gao Y,Kim H.Catalytic degraders effectively address kinase site mutations in EML4-ALK oncogenic fusions.J Med Chem2023;66:5524-35

[136] Ramirez M,Steininger RJ.Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.Nat Commun2016;7:10690 PMCID:PMC4762880

[137] Cabanos HF.Emerging insights into targeted therapy-tolerant persister cells in cancer.Cancers2021;13:2666 PMCID:PMC8198243

[138] 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

[139] Mikubo M,Liu G.Mechanism of drug tolerant persister cancer cells: the landscape and clinical implication for therapy.J Thorac Oncol2021;16:1798-809

[140] Voena C,Mastini C.Efficacy of a cancer vaccine against ALK-rearranged lung tumors.Cancer Immunol Res2015;3:1333-43 PMCID:PMC4674335

[141] Awad MM,Blasco RB.Epitope mapping of spontaneous autoantibodies to anaplastic lymphoma kinase (ALK) in non-small cell lung cancer.Oncotarget2017;8:92265-74 PMCID:PMC5696179

[142] Mota I,Mastini C.ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer.Nat Cancer2023;4:1016-35

[143] Elsayed M.Therapeutic sequencing in ALK⁺ NSCLC.Pharmaceuticals2021;14:80 PMCID:PMC7912146

[144] Nagasaka M.Lorlatinib should be considered as the preferred first-line option in patients with advanced ALK-rearranged NSCLC.J Thorac Oncol2021;16:532-6

[145] Griesinger F,Pöttgen C,Eberhardt WEE.Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms.Oncotarget2018;9:35181-94 PMCID:PMC6205553

[146] Mok T,Gadgeel SM.Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.Ann Oncol2020;31:1056-64

[147] Kilickap S,Dursun OU,Karadurmus N.Safety of lorlatinib in ALK-positive non-small-cell lung cancer and management of central nervous system adverse events.Future Oncol2023;19:2003-12

[148] Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med2022;386:1973-85 PMCID:PMC9844511

[149] Reck M,Harpole D.LBA59 Associations of ctDNA clearance and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase III AEGEAN trial.Ann Oncol2023;34:S1300

[150] Lin JJ,Yoda S.Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer.J Clin Oncol2018;36:1199-206 PMCID:PMC5903999

[151] Drilon A, Siena S, Dziadziuszko R, et al; trial investigators. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.Lancet Oncol2020;21:261-70 PMCID:PMC7811790

[152] Lin CC,Lu S.A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas.Br J Cancer2019;121:131-8 PMCID:PMC6738096

[153] Solomon B,Dziadziuszko R.LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC).Ann Oncol2023;34:S1295-6

[154] Leonetti A,Boni L.Phase II, open-label, single-arm, multicenter study to assess the activity and safety of alectinib as neoadjuvant treatment in surgically resectable stage III ALK-positive NSCLC: ALNEO trial.Clin Lung Cancer2021;22:473-7

[155] Lee J,Pass H.P2.01-06 NAUTIKA1 study: preliminary efficacy and safety data with neoadjuvant alectinib in patients with stage IB-III ALK+ NSCLC.J Thorac Oncol2023;18:S297-8

[156] Paz-Ares L,Lisberg AE.1314MO TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs).Ann Oncol2023;34:S755-6

[157] Petrylak DP,Vogelzang NJ.First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI).J Clin Oncol2020;38:15

[158] Lin JJ,Zhu VW.Efficacy of platinum/pemetrexed combination chemotherapy in ALK-positive NSCLC refractory to second-generation ALK inhibitors.J Thorac Oncol2020;15:258-65 PMCID:PMC7058505