Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance

Tatsushi Kodama; Toshiyuki Tsukaguchi; Miyuki Yoshida; Osamu Kondoh; Hiroshi Sakamoto

doi:10.1016/j.canlet.2014.05.020

Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance

Cancer Lett. 2014 Sep 1;351(2):215-21. doi: 10.1016/j.canlet.2014.05.020. Epub 2014 Jun 2.

Authors

Tatsushi Kodama¹, Toshiyuki Tsukaguchi¹, Miyuki Yoshida¹, Osamu Kondoh¹, Hiroshi Sakamoto²

Affiliations

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

PMID: 24887559
DOI: 10.1016/j.canlet.2014.05.020

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.

Keywords: ALK; ALK inhibitor; Alectinib; Drug resistance; NSCLC; Xenograft model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carbazoles / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Crizotinib
Drug Resistance, Neoplasm
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Mice
Mice, SCID
Piperidines / pharmacology*
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / pharmacology
Pyridines / pharmacology
Random Allocation
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / genetics
Treatment Outcome
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Carbazoles
Piperidines
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Crizotinib
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
alectinib