Crizotinib Resistance Arises through Multiple Mechanisms Available to Purchase

Patients with non–small cell lung cancer (NSCLC) harboring the EML4-ALK fusion oncogene are highly responsive to the ALK tyrosine kinase inhibitor crizotinib but inevitably relapse. Katayama and colleagues and Doebele and colleagues cataloged the mechanisms of acquired drug resistance in biopsies from EML4-ALK–positive NSCLC patients who progressed while on crizotinib. In 22% to 36% of patients, sequencing of the ALK kinase domain exons identified multiple mutations resulting in distinct amino-acid substitutions or insertions that are predicted to impair crizotinib binding. Katayama and colleagues found that the different ALK mutants varied in their sensitivity to second-generation ALK inhibitors, with the 1151Tins mutation showing resistance to all ALK inhibitors tested. However, the HSP90 inhibitor 17-AAG potently suppressed the growth of cells harboring any of the ALK kinase mutants in vitro. Another 6% to 9% of the crizotinib-resistant patients had acquired high-level amplification of the EML4-ALK fusion gene. To characterize the...