Abstract 3722: The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and crizotinib-resistant MET-driven renal tumor models

Abstract

Abstract Introduction: The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers including papillary renal carcinoma, making it a prime anti-cancer 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. Small molecule HSP90 inhibitors cause HSP90 to dissociate from its client proteins, resulting in their destabilization and eventual degradation. HSP90 inhibitors have been validated in numerous preclinical tumor models and have shown promising activity in several clinical trials. Given the distinct mechanisms of action of TKI and HSP90 inhibitors, we evaluated the synergistic effects of these two drugs on both TKI-sensitive and TKI-resistant MET-driven tumor models. Methods: We tested efficacy of the MET TKI crizotinib, the HSP90 inhibitor ganetespib and their combination in MKN45, wild-type MET-overexpressed cell line and MET-Y1248H, TKI-resistant mutant MET- verexpressed cell line in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in xenograft models. Results: MET is an HSP90-dependent kinase, and we show that HSP90 preferentially interacts with and stabilizes activated MET, 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 TKI-sensitive MET-driven tumor models. Unexpectedly, low-dose ganetespib also partially restores crizotinib sensitivity, in vitro and in vivo, to cells and tumors expressing TKI-resistant MET mutants. Conclusion: Our findings support the use of HSP90 inhibitors to overcome or delay the initiation of resistance to MET TKI, and they provide the basis for clinical evaluation of this combination in patients with MET-driven papillary renal cancer. Citation Format: Naoto Miyajima, Tomoshige Akino, Kunihiko Tsuchiya, Satoru Maruyama, Takashige Abe, Nobuo Shinohara, Katsuya Nonomura, Len Neckers. The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and crizotinib-resistant MET-driven renal tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3722. doi:10.1158/1538-7445.AM2014-3722