Abstract 5466: The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma

Abstract

Abstract RAF kinase inhibitors have shown substantial therapeutic effects in patients with BRAF-mutant melanoma. However, despite impressive initial responses, therapeutic effects are often temporary due to acquired resistance. This resistance highlights the need to identify therapeutic approaches to improve the durability of responses to RAF inhibitors. In this study, we demonstrate that a novel inhibitor of p53-Mdm2 interaction, NVP-CGM097, causes marked reduction of melanoma cell viability. The activation of p53 signaling and consequent reduction in cell viability required wild-type p53, but was independent of BRAF status. Moreover, combined inhibition of Mdm2, using NVP-CGM097, and BRAF using NVP-LGX818, synergistically inhibited the viability of BRAF mutant melanoma cells in vitro and tumor growth in vivo. NVP-CGM097 caused induction of p21 and Bax, while NVP-LGX818 did not. Instead, NVP-LGX818 caused induction of p27 and Bim. Therefore, together they induced a complementary set of anti-proliferative and apoptosis stimulating molecules, which resulted in strong synergistic antitumor effects. In vivo, the combination treatment resulted in sustained tumor regressions and markedly prolonged survival relative to either single agent. Collectively, these data show that activation of p53, through inhibition of Mdm2, leads to antitumor effects in melanoma. Furthermore, the data show that concomitant activation of tumor suppressor p53 and inhibition of BRAF synergistically suppresses melanoma growth. Therefore, combined inhibition of Mdm2 and BRAF in melanoma may provide an effective therapeutic modality capable of overcoming the resistance observed with the BRAF inhibitor monotherapy and thus lead to more durable responses in the clinic. Citation Format: Hui Qin Wang, Matthew Zubrowski, Erling Emerson, Elina Pradhan, Sébastien Jeay, Marion Wiesmann, Giordano Caponigro, Jens Wuerthner, Robert Schlegel, Z. Alexander Cao, Alan Huang, Ensar Halilovic. The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma. [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 5466. doi:10.1158/1538-7445.AM2014-5466