Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non―Small Cell Lung Cancer

• Published in: Clinical cancer research 2012-03, Vol.18 (5), p.1472-1482
• Main Authors: DOEBELE, Robert C, PILLING, Amanda B, VARELLA-GARCIA, Marileila, ROSS CAMIDGE, D, AISNER, Dara L, KUTATELADZE, Tatiana G, LE, Anh T, WEICKHARDT, Andrew J, KONDO, Kimi L, LINDERMAN, Derek J, HEASLEY, Lynn E, FRANKLIN, Wilbur A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line; Disease Progression; DNA Copy Number Variations; Drug Resistance, Neoplasm - genetics; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical sciences; Models, Molecular; Mutation; Oncogene Proteins, Fusion - genetics; Pharmacology. Drug treatments; Pneumology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Structure, Tertiary; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; ras Proteins - genetics; Receptor Protein-Tyrosine Kinases - chemistry; Receptor Protein-Tyrosine Kinases - genetics; Receptor, Epidermal Growth Factor - genetics; Translocation, Genetic; Tumors of the respiratory system and mediastinum
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-2906

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). 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. 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. Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.