Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma

Acta Pharmacologica Sinica
Ming-Zhao GaoLi-Guang Lou

Abstract

BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors. Notably, knockdown of rpS6 in these cells effectively downregulated G1 phase-related proteins, including RB, cyclin D1, and CDK6, induced cell cycle arrest, and inhibited proliferation, suggesting that aberrant modulation of rpS6 phosphorylation contributed to the acquired resistance. Interestingly, RSK inhibitor had little effect on rpS6 phosphorylation and cell proliferation in resistant cells, whereas P70S6K inhibitor showed stronger inhibitory effects on rpS6 phosphorylation and cell proliferation in resistant cells than in parental cells. Thus regulation of rpS6 phosphorylation, which is predominantly mediated by BRAF/MEK/ERK/RSK signali...Continue Reading

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Citations

Nov 11, 2019·Life Science Alliance·Reema BaskarSean C Bendall
Jun 25, 2020·Journal of the European Academy of Dermatology and Venereology : JEADV·S Osella-AbateS Ribero
Nov 26, 2020·Neuro-oncology Advances·Karisa C SchreckChristine A Pratilas
Jun 8, 2021·Cancer Treatment Reviews·Tijana RandicStephanie Kreis
Dec 19, 2021·Journal of Cellular and Molecular Medicine·Bo ZhangNeng-Ming Lin

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Methods Mentioned

BETA
fluorescence-activated cell sorting
electrophoresis
flow cytometry
chip
transfection

Software Mentioned

GraphPad Prism
CellQuest Pro
ModFit LT

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