Abstract 4331: Lowering glucose increases nutlin-3 toxicity against melanomas irrespective of BRAF,NRAS or p53 mutations

Abstract

Abstract BACKGROUND: Melanomas are commonly characterized by mutually exclusive BRAF V600Emutations (∼60%) or NRASQ61 mutations (∼15%). Although targeted therapy with vemurafenib is initially efficient in melanoma with BRAF mutations, tumor recurrence occurs including emergence of resistant melanoma cells with secondary N-RASQ61K mutations. Recently it was demonstrated that nutlin-3, an HDM2 antagonist capable of restoring p53 tumor suppressor function synergized with vemurafenib against BRAF V600E wt p53 melanomas. Although nutlin-3 was initially believed to be non-genotoxic, it can originate p53 mutations which are infrequent in primary melanomas. OBJECTIVES: Since tumor growth increases metabolic demand and glucose consumption, we investigated whether lowering glucose with glycolytic inhibitors increases nutlin-3 toxicity against melanomas irrespective of BRAF, NRAS or p53 status. EXPERIMENTAL: Metabolic activity/proliferation of melanoma cells harbouring BRAF, NRAS or p53 mutations was quantitated by fluorometric studies, crystal violet staining was used to determine differential cell survival, and mechanisms of cell death were studied by protein array immune blotting. RESULTS: Restricting glucose increases nutlin-3 toxicity against wt p53 melanoma cells harbouring BRAF or NRAS, even if the latter have p53 mutations. Responses occur through mechanisms dependent and independent of p53 serine 15-phosphorylation and p21/CIP1/CDNK1A. CONCLUSION: Elimination of melanoma cells irrespective of their BRAF, NRAS or p53 mutational status may be helped by joint use of glucose-lowering agents together with nutlin-3. Citation Format: Manuel Rieber, Valery Chavez-Perez, Mary Strasberg-Rieber. Lowering glucose increases nutlin-3 toxicity against melanomas irrespective of BRAF,NRAS or p53 mutations. [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 4331. doi:10.1158/1538-7445.AM2014-4331