| Literature DB >> 26698910 |
Ted W Johnson1, Jeffrey A Engelman1, Alice T Shaw1, Luc Friboulet1, Ignaty Leshchiner1, Justin F Gainor1, Simon Bergqvist1, Alexei Brooun1, Benjamin J Burke1, Ya-Li Deng1, Wei Liu1, Leila Dardaei1, Rosa L Frias1, Kate R Schultz1, Jennifer Logan1, Leonard P James1, Tod Smeal1, Sergei Timofeevski1, Ryohei Katayama1, A John Iafrate1, Long Le1, Michele McTigue1, Gad Getz1.
Abstract
In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).Entities:
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Year: 2015 PMID： 26698910 PMCID： PMC4773904 DOI： 10.1056/NEJMoa1508887
Source DB: PubMed Journal: N Engl J Med ISSN： 0028-4793 Impact factor: 91.245