Abstract 5108: The Hsp90 inhibitor ganetespib is a potent chemosensitizer in preclinical colorectal cancer models

Abstract

Abstract Background: More than half of all individuals diagnosed with colorectal cancer (CRC) will develop metastases and require chemotherapy. These treatments have significantly improved overall patient survival; however, drug resistance is a frequent cause of treatment failure often due to alteration in cell cycle regulators or DNA damage repair. The molecular chaperone HSP90 plays an important role in both processes by stabilizing proteins required for pathway activation and maintenance. Here, we sought to determine if HSP90 inhibition by the investigational drug ganetespib could enhance the activity of standard chemotherapeutics utilized in CRC in order to extend responses and bypass/delay drug resistance. Results: Western blot analyses revealed that low nanomolar ganetespib treatment promoted the degradation of a number of proteins involved in proliferation (EGFR, PDGFR, PI3-K/AKT/p70 S6 kinase, cMET and MAPK), survival (MCL1), anigiogenesis (VEGFR), cell cycle check points and DNA repair (CDK1, CHK1, Survivin, WEE1) in a panel of CRC cell lines. This activity directly correlated with G0/G1 cell cycle arrest and loss of CRC cell viability (average IC50 in 19 CRC cell lines = 43 nM). In vitro combination of ganetespib with conventional chemotherapies (cisplatin, oxaliplatin, 5-FU) augmented the accumulation of DNA damage (phospho-H2AX) and mitotic catastrophe more effectively over monotherapy alone in HCT116, HT29 and LoVo CRC cells. Ganetespib also sensitized CRC cells to ionizing radiation by inducing aberrant mitosis and enhanced DNA damage/fragmentation, resulting in a significant increase in apoptosis. In vivo, ganetespib displayed comparable antitumor activity as capecitabine, cisplatin, and bevacizumab in human CRC tumor xenografts, with treatment/control values of ∼50 indicative of slowly progressive disease. Combining ganetespib with capecitabine resulted in significant tumor regression (T/C = -52, p<0.01). Further, ganetespib improved the tumor suppressive capacity of cisplatin and bevacizumab. Conclusions: The HSP90 inhibitor ganetespib promotes the destabilization of numerous proteins essential for tumor growth and survival as well as those involved in chemotherapeutic resistance. As a result, ganetespib sensitizes colon cancer tumor models to chemotherapy and targeted agents, including VEGF inhibitors. Ganetespib is currently being evaluated in combination with capecitabine and radiation in patients with locally-advanced rectal cancer as part of an open-label, investigator-sponsored Phase 1 clinical study. Citation Format: Suqin He, Don Smith, Manuel Sequeira, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Timothy Korbut, Jaime Acquaviva, Masazumi Nagai, Richard Bates, David A. Proia. The Hsp90 inhibitor ganetespib is a potent chemosensitizer in preclinical colorectal cancer 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 5108. doi:10.1158/1538-7445.AM2014-5108