{"entity":{"id":"paper-gainor-alk-resistance-mutations-cancer-discov-2016","kind":"paper","name":"Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer","aka":[],"tldr":"Rebiopsying 103 patients as each generation of drug failed showed that each drug leaves its own signature of escape mutations, and that whether a mutation is present decides whether the next drug in the sequence will work.","summary":"One hundred and three repeat biopsies from patients with ALK-positive lung cancer progressing on various ALK inhibitors were analysed. Each ALK inhibitor was associated with a distinct spectrum of ALK resistance mutations, and the frequency of ALK G1202R increased significantly after treatment with second-generation agents. Second-generation inhibitors are generally effective after crizotinib even without a crizotinib-resistant ALK mutation, reflecting incomplete inhibition of ALK by crizotinib in many cases. In a series of ceritinib-resistant patient-derived cell lines, the presence of ALK resistance mutations was highly predictive of sensitivity to the third-generation inhibitor lorlatinib, whereas lines without ALK mutations were resistant.","asOf":"2026-09-25","links":[{"label":"Gainor et al., Cancer Discov 2016: 103 repeat biopsies and the resistance mutations of first- and second-generation ALK inhibitors","url":"https://doi.org/10.1158/2159-8290.CD-16-0596"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27432227/"}],"tags":[],"related":["alk-fusion"],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors","cgp","organoids"],"targets":["alk"],"drugs":["crizotinib","ceritinib","alectinib","brigatinib","lorlatinib"],"companies":[],"institutions":["mgh"],"pathways":["resistance-routes-map","rtk-activation","clonal-evolution"],"terms":["resistance","cross-resistance","gene-fusion","biopsy"],"trials":[],"people":["justin-gainor"],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2016,"doi":"10.1158/2159-8290.CD-16-0596","pmid":"27432227","authors":"Gainor JF, Dardaei L, Yoda S, et al.","paperType":"translational","findings":["Each ALK inhibitor generation leaves a distinct spectrum of resistance mutations.","G1202R rises significantly in frequency after second-generation treatment.","Second-generation drugs work after crizotinib whether or not a resistance mutation is present.","Lorlatinib sensitivity in cell lines tracks the presence of an ALK mutation."],"whatItMeans":"It made repeat biopsy and genotyping at progression the standard in ALK-positive lung cancer, because after a second-generation inhibitor the presence or absence of an ALK mutation is what separates patients who should receive a third-generation inhibitor from those who should not.","caveats":["Biopsies come from patients whose disease could be sampled, which selects for accessible lesions.","Cell line predictions were later confirmed in patients but with weaker separation.","Resistance that is ALK-independent was not characterised in detail."],"changedPractice":true,"participants":103},"route":"/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/","neighbours":{"biomarker":[{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","route":"/biomarkers/alk-fusion/"},{"id":"alk-resistance-mutation","kind":"biomarker","name":"ALK kinase-domain resistance mutation (G1202R and the rest)","route":"/biomarkers/alk-resistance-mutation/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"organoids","kind":"technology","name":"Patient-derived organoids","route":"/technologies/organoids/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"}],"drug":[{"id":"alectinib","kind":"drug","name":"Alectinib","route":"/drugs/alectinib/"},{"id":"brigatinib","kind":"drug","name":"Brigatinib","route":"/drugs/brigatinib/"},{"id":"ceritinib","kind":"drug","name":"Ceritinib","route":"/drugs/ceritinib/"},{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"}],"institution":[{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"biopsy","kind":"term","name":"Biopsy","route":"/terms/biopsy/"},{"id":"cross-resistance","kind":"term","name":"Cross-resistance","route":"/terms/cross-resistance/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"}],"person":[{"id":"justin-gainor","kind":"person","name":"Justin F. Gainor","route":"/people/justin-gainor/"}],"journal":[{"id":"cancer-discovery","kind":"journal","name":"Cancer Discovery","route":"/journals/cancer-discovery/"}]}}