Phospho-Proteomic Analysis Of Mek Inhibition In Mutant Nras Melanoma

Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to twenty percent of melanoma patients have an activating mutation in NRAS, a small GTPase. NRAS has several downstream effectors, the most well-characterized is RAF leading to activation of MEK/ERK. While there are no FDA-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. Phase I to III studies of MEK inhibitors in mutant NRAS melanomas have shown disappointing clinical efficacy, the reasons for which are unclear. In 3D systems that mimic the dermal microenvironment, we found a heterogeneous response in our panel of mutant NRAS melanoma cells to the allosteric MEK inhibitor, trametinib. To explore the underlying basis of this heterogeneity, we utilized a high-throughput reverse-phase protein array (RPPA) platform to identify compensatory signaling alterations. The RPPA analysis of phospho-proteomic changes in NRAS mutant melanoma in response to trametinib indicated a compensatory increase in AKT signaling. Interestingly, we detected a decrease in mitogen inducible gene 6 (MIG6), a negative regulator of ERBB receptors. The overexpression of MIG6 led to a negative regulation of EGFR (ERBB1) and ERBB2, and subsequent decrease in AKT activation. Conversely, the depletion of MIG6 increased EGFR and ERBB2 signaling. Either depletion of MIG6 or addition of EGF increased migration of NRAS mutant cells treated with trametinib, an invasive phenotype that may mitigate the negative effects of trametinib on cell growth. Our results indicate a potential role for the combined inhibition of EGF/ERBB receptors and MEK in NRAS mutant melanoma patients. Citation Format: Ha Linh Vu, Michael A. Davies, Andrew E. Aplin. Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-13.