p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis.

Autor:	Theodosakis N; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA., Micevic G; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA., Langdon CG; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA., Ventura A; Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Dermatology, University of Rome Tor Vergata, Rome, Italy., Means R; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA., Stern DF; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA., Bosenberg MW; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA. Electronic address: marcus.bosenberg@yale.edu.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2017 Oct; Vol. 137 (10), pp. 2187-2196. Date of Electronic Publication: 2017 Jun 07.
DOI:	10.1016/j.jid.2016.12.033
Abstrakt:	Despite improvements in survival in metastatic melanoma with combined BRAF and mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor treatment, the overwhelming majority of patients eventually acquire resistance to both agents. Consequently, new targets for therapy in resistant tumors are currently being evaluated. Previous studies have identified p90 subfamily of ribosomal S6 kinase (p90RSK) family kinases as key factors for growth and proliferation, as well as protein synthesis via assembly of the 7-methyl-guanosine triphosphate cap-dependent translation complex. We sought to evaluate inhibitors of p90RSK family members: BI-D1870 and BRD7389, for their ability to inhibit both proliferation and protein synthesis in patient-derived melanoma cell lines with acquired resistance to combined treatment with the BRAF inhibitor vemurafenib and the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor selumetinib. We found that the RSK inhibitors blocked cell proliferation and protein synthesis in multiple dual-resistant melanoma lines. In addition, single agent RSK inhibitor treatment was effective in drug-naïve lines, two of which are innately vemurafenib resistant. We also used Reverse Phase Protein Array screening to identify differential protein expression that correlates with BI-D1870 sensitivity, and identified prognostic biomarkers for survival in human melanoma patients. These findings establish p90RSK inhibition as a therapeutic strategy in treatment-resistant melanoma and provide insight into the mechanism of action. (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu