Abstract B19: Modulation of cytotoxic effects of vemurafenib by chloroquine in malignant melanoma cells G-361: Role of dermcidin

Abstract

Abstract Dermcidin (DCD) is a candidate oncogene localized at 12q13.1 and co-amplified with multiple oncogenes in many tumor cells, including breast carcinomas and melanomas. DCD is one of the 100 gene signature for melanomas. To further understand the role of DCD on growth, survival and progression of melanoma cells, we selected G-361 melanoma cell clones expressing shRNA to DCD and established in vitro and in vivo models. In this study we evaluated the pharmacologic effects of vemurafenib (BRAFV600E inhibitor) and chloroquine (autophagy inhibitor) in cell viability and tumor growth of two melanoma cell lines identified as G-361 pLKO, which expresses DCD and BRAFV600E, and G-361 IBC I which express shRNA to silence DCD constitutively. Vemurafenib induces features of stress-induced senescence in addition to apoptosis. G-361 melanoma cells responded to vemurafenib (1-2 μM) alone or combined with chloroquine (50-100 μM) which increased apoptosis rates, while decreasing senescent cells expressing β-galactosidase enzyme. Vemurafenib (50 mg/kg / 21 days) inhibited melanoma growth in immunodeficient mice dependent on DCD expression. Chloroquine (30 mg/kg) in combination with vemurafenib, accelerated (given at 24-hour interval), and reduced (given at 72 hours interval), melanoma growth. Tumor cells resistant to vemurafenib and chloroquine displayed atypical cell morphology and nuclear histological patterns and diferential expression of melanocytic differentiation biomarkers S100, HMB-45, Melan-A and pancytokeratins. This work confirms the efficacy of vemurafenib and suggests potential adjuvant effects of chloroquine. It also confirms the role of dermcidin as growth factor and oncogene for melanoma cells. Citation Format: Jennifer Montoya Neyra, Jose Belizario. Modulation of cytotoxic effects of vemurafenib by chloroquine in malignant melanoma cells G-361: Role of dermcidin [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B19.