Abstract 5030: Mechanistic insight of differential sensitivity to MEK inhibition

Abstract

Abstract BRAF is mutated in melanomas and plays a role in tumorigenesis. Although depletion of oncogenic BRAF resulted in tumor regression in mouse melanoma model, clinical development of anti-BRAF signaling therapy has not been successful up to date. We performed a search of genomic alterations that are correlated to sensitivity to MEK inhibitors using human melanoma cell lines. Multiple genetic changes are identified to be of predictive value. Based on our genetic analysis, p53 is identified to be a major factor that controls sensitivity to MEK inhibitors. p53 is a major tumor suppressor and is mutated in a small set of human melanomas. Here, we show that p53 is inducible in most human melanoma cell lines in response to DNA damage. MDM2 inhibitor Nutlin-3a increases p53 protein expression as well as its activities in melanoma cells. Addition of nutlin-3a significantly increases sensitivity of melanoma cells to MEK inhibitor U0126 induced cell death or cell cycle arrest. In addition, knockdown p53 by specific shRNAs effectively rescues apoptosis induced by MEK inhibitor and/or p53 activation. This data suggests that p53 activity is required for cell death induced by MEK inhibitors and/or p53 activators. In conclusion, p53 is identified from a genetic screen for MEK inhibitor sensitivity. p53 reactivation potentiates cell death induced by BRAF/MEK signaling inhibitory agents in a group of melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5030.