B-Raf Status Predicts Response To Pharmacological Activation Of P53 In Melanoma

The formulation of highly-potent and specific inhibitors of the MAPK pathway has yielded several promising candidates and these are currently under advanced clinical development; however, early data suggests that inhibition of the MAPK pathway will not be sufficient to elicit sustained tumor regression in malignant melanoma. Thus, other pathways likely need to be therapeutically exploited to achieve sustained responses in melanoma patients. Because the tumor suppressor protein p53 is functional, yet inactive, in nearly 100% of melanomas, we sought to identify novel pharmacological activators of p53 in melanoma. To accomplish this goal, we employed a high-throughput screening strategy that identified hycanthone, a compound previously characterized for anti-schistosomal activity, as a specific activator of p53 function. In vitro characterization of hycanthone demonstrated that it activates the p53-transcriptional response leading to cell cycle arrest and subsequent apoptosis in a panel of melanoma cell lines harboring wild-type p53; these effects are largely absent in isogenic cells expressing p53 shRNA or alternative lines expressing mutant p53. Screening of a substantial panel of cell lines revealed that activation of p53 initiated anti-melanoma effects exclusively in cells that expressed mutant Braf, indicating that activated MAPK signaling may serve as a correlate to predict response to pharmacological activators of p53 in melanoma. However, additional experimentation has demonstrated that, instead, it is the presence of mutations in Braf, rather than the resultant MAPK activity, that predicts response to p53 activation. Studies investigating the mechanistic details governing this biological phenomenon are ongoing. Collectively, our data indicate that reactivation of p53 in melanoma, like multiple other tumors, can elicit an anti-tumor phenotype; however, this response is negatively modulated by the expression of mutant Braf, which would suggest that patients should be prospectively genotyped to identify potential responders to p53 reactivators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 587. doi:10.1158/1538-7445.AM2011-587