Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer

Tatsushi Kodama; Toshiyuki Tsukaguchi; Yasuko Satoh; Miyuki Yoshida; Yoshiaki Watanabe; Osamu Kondoh; Hiroshi Sakamoto

doi:10.1158/1535-7163.MCT-14-0274

Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer

Mol Cancer Ther. 2014 Dec;13(12):2910-8. doi: 10.1158/1535-7163.MCT-14-0274. Epub 2014 Oct 27.

Authors

Tatsushi Kodama¹, Toshiyuki Tsukaguchi¹, Yasuko Satoh¹, Miyuki Yoshida¹, Yoshiaki Watanabe¹, Osamu Kondoh¹, Hiroshi Sakamoto²

Affiliations

¹ Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
² Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan. sakamotohrs@chugai-pharm.co.jp.

PMID: 25349307
DOI: 10.1158/1535-7163.MCT-14-0274

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.

MeSH terms

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

Substances

Antineoplastic Agents
CCDC6 protein, human
Carbazoles
Cytoskeletal Proteins
Oncogene Proteins, Fusion
Piperidines
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-ret
RON protein
ROS1 protein, human
Receptor Protein-Tyrosine Kinases
alectinib