Abstract 3433: Deciphering the mechanism of synergy between the Heat Shock Protein 90 inhibitor retaspimycin HCl and docetaxel in preclinical models of non-small cell lung cancer.

Abstract

Abstract Heat Shock Protein 90 (Hsp90) has emerged as an attractive target in cancer therapy given its role in promoting the activity and stability of a host of oncogenic client proteins. Due to the functional diversity of client proteins, Hsp90 inhibitors have the potential to disrupt multiple oncogenic signaling pathways to mediate cancer cell death. Retaspimycin HCl (IPI-504) is a potent, selective inhibitor of Hsp90 that has single agent activity predominantly in EML4-ALK positive non-small cell lung cancers (NSCLC). Retaspimycin HCl also recently demonstrated clinical activity in a Phase Ib trial when combined with docetaxel in patients with previously treated NSCLC without prospective selection for mutations or rearrangements. This trial demonstrated an overall response rate (ORR) of 26% (n=23) to combination therapy (Riely et al., ASCO, 2011), indicating an enhanced response compared to historical data with single agent docetaxel (ORR of 8%) (Hanna et al., JCO, 2004). To further evaluate activity of this drug combination, a double-blind, randomized Phase II trial is being conducted in NSCLC patients with a smoking history.In support of this trial, preclinical studies are being performed to determine the mechanism of action (MOA) of retaspimycin HCl and docetaxel in combination. To this end, a panel of NSCLC cell lines was screened for sensitivity to combination treatment, leading to identification of a subset of cell lines in which these drugs act in synergy to enhance cell death. Synergy with fixed and non-fixed drug ratios was assessed using the Chou-Talalay method to determine the combination index (CI). To then investigate the mechanism of synergy, an unbiased “stable isotope labeling by amino acids in cell culture” (SILAC) proteomic approach was employed to identify Hsp90 client proteins depleted by combination treatment. Several mitotic regulators, including components of the anaphase promoting complex (APC), were specifically downregulated in response to combination treatment, leading to the hypothesis that combination treatment mediates cell death by prolonging mitosis. Supporting this hypothesis, cells treated with retaspimycin HCl/docetaxel demonstrated a synergistic increase in the percentage of mitotic cells, as assessed by phospho-histone H3 staining, and accumulation of the APC substrates, securin and Cyclin B. Xenograft models of NSCLC demonstrated tumor regression in response to combination treatment, and pharmacodynamic studies are underway to examine the molecular basis for this regression. These preclinical data, together with biomarker investigation in the ongoing Phase II trial, may lead to an improved ability to identify NSCLC patients that are more likely to respond to combination treatment with retaspimycin HCl and docetaxel, and may inform the use of retaspimycin HCl in other combinations and indications. Citation Format: Katie O'Callaghan, Brenda C. O'Connell, Bonnie Tillotson, Mark Douglas, Howard Stern, Kip A. West, Janid A. Ali, Paul Changelian, Karen McGovern, Vito J. Palombella, Christian C. Fritz, Jeff L. Kutok. Deciphering the mechanism of synergy between the Heat Shock Protein 90 inhibitor retaspimycin HCl and docetaxel in preclinical models of non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3433. doi:10.1158/1538-7445.AM2013-3433