Abstract 1792: Identification of synergistic drug combinations with the oral HSP90 inhibitor Debio 0932 in non-small cell lung cancer and renal cell cancer

Abstract

Abstract Background: Drug resistance is a major problem in cancer therapy, which can be addressed by simultaneously targeting multiple critical nodes of the signalling networks controlling growth and survival of cancer cells. One such approach is to target heat shock protein 90 (HSP90), a chaperone for many potent oncogenic proteins involved in proliferation, survival, invasion, metastasis and angiogenesis. Pharmacologic inhibition of HSP90 results in the proteasomal degradation of client oncoproteins thereby eliminating their oncogenic activity. The oral HSP90 inhibitor Debio 0932 displays favorable pharmacologic features. The goal of this study was to identify novel synergistic drug combinations for Debio 0932 in non-small cell lung cancer (NSCLC) and renal cell cancer (RCC) which would support the clinical development of Debio 0932 in those two indications. Material and Methods: For NSCLC, an in vitro high-throughput combination screen was performed using 6 human NSCLC cell lines bearing various genetic alterations, where Debio 0932 was combined pairwise with 128 commercially available oncology compounds in a cell viability assay. Some additional compounds not included in the panel were also tested independently. For RCC, combination of Debio 0932 with several selected standard-of-care drugs was analyzed on a panel of 8 human RCC cell lines. Synergy was assessed by using an AUC-based curve shift analysis method or according to the Chou-Talalay equation. A selection of synergistic drug combinations was further studied using tumor xenograft mouse models of human NSCLC and RCC. Results: In NSCLC, anti-proliferative synergism with Debio 0932 was observed in vitro in combination with the standard-of-care drugs docetaxel, paclitaxel or gemcitabine, as well as with mTOR inhibitors. In RCC cell lines, combinations of Debio 0932 with RCC standard-of-care drugs also displayed anti-proliferative synergy. The synergy observed in vitro was further confirmed in mouse xenografts of human NSCLC and RCC cell lines, where the drug combinations caused marked anti-tumor activity that was superior to either monotherapy. Conclusion: Several synergistic drug combinations were identified for the HSP90 inhibitor Debio 0932 in NSCLC and RCC. These findings underline the feasibility of using in vitro high-throughput screening for the discovery of novel drug combinations with increased in vivo anti-tumor efficacy . Furthermore, they provide a rationale for the combination of Debio 0932 with standard-of-care drugs in NSCLC and RCC and are the basis for ongoing clinical trials in several cancer types. Citation Format: Casey G. Langdon, Norbert Wiedemann, Hélène Maby-El Hajjami, Mathew A. Held, James T. Platt, Grégoire Vuagniaux, Marcus W. Bosenberg, David F. Stern, Frédéric Lévy. Identification of synergistic drug combinations with the oral HSP90 inhibitor Debio 0932 in non-small cell lung cancer and renal cell cancer. [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 1792. doi:10.1158/1538-7445.AM2014-1792