title: Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance.
abstract: The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. Here we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in models of crizotinib resistance. Alectinib led to tumor size reduction in EML4-ALK-positive xenograft tumors that failed to regress fully during the treatment with crizotinib. In addition, alectinib inhibited the growth of some EML4-ALK mutant-driven tumors, including the G1269A model. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsukaguchi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kondoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan. Electronic address: sakamotohrs@chugai-pharm.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib
keywords: ALK; ALK inhibitor; Alectinib; Drug resistance; NSCLC; Xenograft model