title: Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer.
abstract: Alectinib/CH5424802 is a known inhibitor of anaplastic lymphoma kinase (ALK) and is being evaluated in clinical trials for the treatment of ALK fusion-positive non-small cell lung cancer (NSCLC). Recently, some RET and ROS1 fusion genes have been implicated as driver oncogenes in NSCLC and have become molecular targets for antitumor agents. This study aims to explore additional target indications of alectinib by testing its ability to inhibit the activity of kinases other than ALK. We newly verified that alectinib inhibited RET kinase activity and the growth of RET fusion-positive cells by suppressing RET phosphorylation. In contrast, alectinib hardly inhibited ROS1 kinase activity unlike other ALK/ROS1 inhibitors such as crizotinib and LDK378. It also showed antitumor activity in mouse models of tumors driven by the RET fusion. In addition, alectinib showed kinase inhibitory activity against RET gatekeeper mutations (RET V804L and V804M) and blocked cell growth driven by the KIF5B-RET V804L and V804M. Our results suggest that alectinib is effective against RET fusion-positive tumors. Thus, alectinib might be a therapeutic option for patients with RET fusion-positive NSCLC.
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: Yasuko
authors.initials: Y
authors.lastname: Satoh
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: Yoshiaki
authors.initials: Y
authors.lastname: Watanabe
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. sakamotohrs@chugai-pharm.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C088832:CCDC6 protein, human; D002227:Carbazoles; D003598:Cytoskeletal Proteins; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C080835:RON protein; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib