• Major finding: ALK gene alterations or activation of other RTKs can drive crizotinib resistance.

  • Clinical relevance: ALK mutants vary in sensitivity to second-generation ALK inhibitors.

  • Impact: Second-line therapies should be tailored to individual crizotinib resistance mechanisms.

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 underlying resistance mechanisms in the remaining patients, the teams screened for mutations in a panel of cancer-related genes using a multiplexed genotyping platform and screened for receptor tyrosine activation (RTK) in crizotinib-resistant cells using phospho-RTK arrays. These approaches identified EGFR, KIT, and RAS activation as bypass mechanisms mediating acquired resistance in crizotinib-refractory patients. Notably, some patients appeared to have acquired ALK mutations, fusion gene amplifications, and/or RTK-activating genetic lesions simultaneously. Although it is clear that additional means of crizotinib resistance remain to be identified, these findings illustrate the heterogeneity and redundancy of drug resistance mechanisms in EML4-ALK–positive NSCLCs and indicate that second-generation ALK inhibitors, HSP90 inhibitors, and combination RTK inhibitor therapy may need to be considered in relapsed patients on a case-by-case basis.

Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 2012;4:120ra17.

Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012 Jan 10. [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.