Abstract 5111: Integrative phospho-proteomic and genomic analyses identify AXL as a potential biomarker and therapeutic target for NRAS-mutated melanoma

Abstract

Abstract Currently, few therapeutic options exist for the 15-20% of patients whose melanomas harbor activating mutations in NRAS. Here, we have used comprehensive phospho-proteomic and genomic analysis to characterize the patterns of intracellular signaling in a panel of NRAS and BRAF-mutated melanoma cell lines, with the goal of identifying new biomarkers and therapeutic targets for NRAS mutated melanomas. Our preliminary analyses showed BRAF mutated melanomas to have less diverse intracellular signaling than the NRAS group, which tended to have constitutive phosphorylation in a wide-range of receptor tyrosine kinases (RTKs), such as c-MET, EGFR, HER2 and c-Abl. Although these patterns of RTK activity were heterogeneous across the NRAS mutated melanoma cell line panel, all of the NRAS mutated cell lines examined showed constitutive activity in the receptor tyrosine kinase Axl. A role for Axl in the oncogenic behavior of NRAS mutated melanomas was suggested by array CGH studies showing genomic amplification of Axl in a significant fraction of the NRAS mutated melanoma cell lines and by Western Blot experiments demonstrating increased expression of Axl and its ligand Gas6. Mass spectrometry analysis and immunoprecipitation revealed Axl to be constitutively phosphorylated at the Tyr702 autophosphorylation site in NRAS mutated melanoma cell lines only. Functionally, siRNA knockdown and pharmacological inhibition of Axl impaired the survival and invasion of NRAS mutated melanoma cell lines grown under 3D organotypic cell culture conditions. Studies are ongoing to confirm the role of Axl in the initiation and progression of melanomas harboring NRAS mutations and determine whether Axl constitutes a therapeutic target for this melanoma sub-group. 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 5111. doi:10.1158/1538-7445.AM2011-5111