Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer
- PMID: 22235099
- PMCID: PMC3311875
- DOI: 10.1158/1078-0432.CCR-11-2906
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer
Abstract
Purpose: Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC).
Experimental design: We analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib.
Results: Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism.
Conclusions: Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.
Conflict of interest statement
Conflict of Interest Statement: RCD has research grants from Pfizer, Eli Lilly, and ImClone. RCD and MVG have received speaker’s fees from Abbott Molecular. RCD, MVG, DRC, KLK, AJW, and DLA have served as consultants for Pfizer. MVG has served as a consultant for Abbott Molecular. DRC has served as a consultant/advisory board member for Chugai, Ariad, and Eli Lilly. DLA has served as a consultant for GSK.
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