| 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) |
| URI: | http://hdl.handle.net/2115/57870 |
| 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)
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