Abstract A14: Hyperactivation of RSK1 is a hallmark of metastatic nodular melanoma

Abstract

Abstract It is generally accepted that superficial spreading (SSM) and nodular melanoma (NM), the most common melanoma histologic subtypes, are biologically indistinct once they invade and metastasize. Consequently, targeted therapy is dictated by the mutational profile of metastatic disease, regardless of the histologic subtype of the primary melanoma. Here, we show that p90 ribosomal S6 kinase (RSK1) is constitutively phosphorylated in human melanoma cell lines derived from NM but not SSM. Significantly, metastases from primary NM patients showed p-RSK1 overexpression and a distinct metalloproteinase profile compared with metastases from primary SSM patients. Interestingly, p-RSK1 hyper-activation could not be solely explained by MAPK activation due to BRAF mutations. We show that NM-derived cell lines were more sensitive to genetic and pharmacological RSK1 inhibition than SSM-derived cell lines. Using a zebrafish model, we demonstrate that activated RSK1 significantly accelerates melanoma progression. In addition, RNAseq revealed up-regulation of extracellular matrix degradation, cell migration, and cell proliferation genes in the RSK1 mutant-expressing tumors. Together, our data demonstrate that metastatic melanoma originating from different histologic subtypes might depend on distinct oncogenic pathways. Data also support constitutive RSK1 activation as a driver of nodular metastatic melanoma, a finding that supports the concept of subtype-specific melanoma therapy. Citation Format: Amel Salhi, Joshua A. Farhadian, Keith M. Giles, Eleazar C. Vega-Saenz de Miera, Ines Pires Da Silva, Caitlin Bourque, Karen Yeh, Sagar Chhangawala, Jinhua Wang, Fei Ye, David Y. Zhang, Eva Hernando-Monge, Yariv Houvras, Iman Osman. Hyperactivation of RSK1 is a hallmark of metastatic nodular melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A14.