title: Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib.
abstract: Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.
authors.affiliation: *Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, California; †Division of Hematology Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California; ‡Division of Surgical Oncology, Department of Surgery, University of California Irvine School of Medicine, Orange, California; §Division of Nuclear Medicine, Department of Radiology, University of California Irvine Medical Center, University of California Irvine School of Medicine, Orange, California; and ‖Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Sai-Hong
authors.initials: SH
authors.lastname: Ignatius Ou
authors.forename: Michele
authors.initials: M
authors.lastname: Azada
authors.forename: David J
authors.initials: DJ
authors.lastname: Hsiang
authors.forename: June M
authors.initials: JM
authors.lastname: Herman
authors.forename: Tatiana S
authors.initials: TS
authors.lastname: Kain
authors.forename: Christina
authors.initials: C
authors.lastname: Siwak-Tapp
authors.forename: Cameron
authors.initials: C
authors.lastname: Casey
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010880:Piperidines / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib