RRC ID 64211
Author Kodama T, Tsukaguchi T, Satoh Y, Yoshida M, Watanabe Y, Kondoh O, Sakamoto H.
Title Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer.
Journal Mol Cancer Ther
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.
Volume 13(12)
Pages 2910-8
Published 2014-12-1
DOI 10.1158/1535-7163.MCT-14-0274
PII 1535-7163.MCT-14-0274
PMID 25349307
MeSH Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Carbazoles / administration & dosage Carbazoles / chemistry Carbazoles / pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics* Cell Line, Tumor Cell Proliferation / drug effects Cytoskeletal Proteins / genetics Cytoskeletal Proteins / metabolism Disease Models, Animal Gene Rearrangement* Humans Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Male Mice Models, Molecular Molecular Conformation Mutation Oncogene Proteins, Fusion / antagonists & inhibitors Oncogene Proteins, Fusion / genetics Oncogene Proteins, Fusion / metabolism Piperidines / administration & dosage Piperidines / chemistry Piperidines / pharmacology* Protein Kinase Inhibitors / administration & dosage Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Protein-Tyrosine Kinases / antagonists & inhibitors Proto-Oncogene Proteins / antagonists & inhibitors Proto-Oncogene Proteins c-ret / antagonists & inhibitors Proto-Oncogene Proteins c-ret / chemistry Proto-Oncogene Proteins c-ret / genetics* Receptor Protein-Tyrosine Kinases / antagonists & inhibitors Signal Transduction / drug effects Xenograft Model Antitumor Assays
IF 5.615
Human and Animal Cells Ba/F3(RCB0805) LC-2/ad(RCB0440)