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The HSP90 Inhibitor Ganetespib Synergizes with the MET Kinase Inhibitor Crizotinib in both Crizotinib-Sensitive and -Resistant MET-Driven Tumor Models

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Title: The HSP90 Inhibitor Ganetespib Synergizes with the MET Kinase Inhibitor Crizotinib in both Crizotinib-Sensitive and -Resistant MET-Driven Tumor Models
Authors: Miyajima, Naoto Browse this author
Tsutsumi, Shinji Browse this author
Sourbier, Carole Browse this author
Beebe, Kristin Browse this author
Mollapour, Mehdi Browse this author
Rivas, Candy Browse this author
Yoshida, Soichiro Browse this author
Trepel, Jane B. Browse this author
Huang, Ying Browse this author
Tatokoro, Manabu Browse this author
Shinohara, Nobuo Browse this author →KAKEN DB
Nonomura, Katsuya Browse this author →KAKEN DB
Neckers, Len Browse this author
Issue Date: 1-Dec-2013
Publisher: American Association for Cancer Research
Journal Title: Cancer research
Volume: 73
Issue: 23
Start Page: 7022
End Page: 7033
Publisher DOI: 10.1158/0008-5472.CAN-13-1156
PMID: 24121490
Abstract: The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers. (C)2013 AACR.
Type: article (author version)
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 宮島 直人

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