title: Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80209, USA. robert.doebele@ucdenver.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Pilling
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
authors.forename: Anh T
authors.initials: AT
authors.lastname: Le
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Weickhardt
authors.forename: Kimi L
authors.initials: KL
authors.lastname: Kondo
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Linderman
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D002460:Cell Line; D000077547:Crizotinib; D056915:DNA Copy Number Variations; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D014178:Translocation, Genetic; D018631:ras Proteins / Q000235:genetics
chemical_list: C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins