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|Ref Type||Journal Article|
|Authors||Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR|
|Title||Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2012 Mar 01|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|EML4 - ALK ALK G1269A||Advanced Solid Tumor||resistant||Crizotinib||Preclinical - Cell culture||Actionable||In a preclinical study, transformed cells expressing ALK G1269A in the context of EML4-ALK were resistant to Xalkori (crizotinib) in culture (PMID: 22235099).||22235099|
|EML4 - ALK ALK G1269A||lung non-small cell carcinoma||resistant||Crizotinib||Case Reports/Case Series||Actionable||In a clinical case study, a non-small cell lung carcinoma patient harboring EML4-ALK demonstrated stable disease when treated with Xalkori (crizotinib), but then progressed, and was found to harbor a secondary resistance mutation, ALK G1269A (PMID: 22235099).||22235099|