Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer

By J. Gainor, Leila Dardaei, S. Yoda, L. Friboulet, I. Leshchiner, Ryohei Katayama, I. Dagogo-Jack, S. Gadgeel, Katherine R. Schultz, Manrose Singh and 23 more. Cancer Discovery, 2016

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Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/451d10fda18be4b1f826287a5d681b5bca0f88a1

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In Oncology

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Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2018, background): “ALK mutations are emerging as important resistance mechanisms to ALK TKIs and ALK mutation testing may soon become a routine test at relapse as newer-generation ALK TKIs show differential efficacy against different ALK mutations [55].”