Abstract 2680: Cyclic AMP signaling in melanoma: Paradoxical downregulation of pCREB upon activation of adenylate cyclase confers resistance to MAPK inhibition

Abstract

Abstract Melanoma, which arises from malignant transformation of melanocytes, has proven to be difficult to treat due its intrinsic and acquired resistance for chemotherapy. Although polymorphisms in the melanocortin receptor 1 (MC1R), which result in impairment of cyclic AMP (cAMP) signaling, are associated with increased risk for melanoma development, the role of cAMP signaling in melanoma, specifically in drug resistance, is not fully understood. Given the importance of cAMP signaling in melanocytes proliferation and differentiation, we investigated the role of cAMP signaling in melanoma cell proliferation, survival and drug resistance. We found that upregulation of cAMP signaling, through activation of adenylate cyclase with forskolin (FSK), has both positive and negative effects on proliferation and survival of melanoma cells. The effect of FSK on melanoma proliferation and survival was not dependent on oncogenic (RAS vs. BRAF) mutation. Moreover, upregulation of cAMP conferred resistance to Selumetinib (AZD6244)-mediated MAPK inhibition by restoring the pERK levels. We also show that FSK-mediated resistance is paradoxically related to a downregulation of phosphorylated cAMP Responsive Element Binding Protein (pCREB), suggesting a CREB-independent mechanism of FSK-induced MAPK reactivation in acquired drug resistance. Citation Format: Carlos I. Rodriguez, Vijayasaradhi Setaluri. Cyclic AMP signaling in melanoma: Paradoxical downregulation of pCREB upon activation of adenylate cyclase confers resistance to MAPK inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2680. doi:10.1158/1538-7445.AM2015-2680