BRAF and AXL oncogenes drive RIPK3 expression loss in cancer

PLoS Biology
Ayaz NajafovJunying Yuan

Abstract

Necroptosis is a lytic programmed cell death mediated by the RIPK1-RIPK3-MLKL pathway. The loss of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression and necroptotic potential have been previously reported in several cancer cell lines; however, the extent of this loss across cancer types, as well as its mutational drivers, were unknown. Here, we show that RIPK3 expression loss occurs progressively during tumor growth both in patient tumor biopsies and tumor xenograft models. Using a cell-based necroptosis sensitivity screen of 941 cancer cell lines, we find that escape from necroptosis is prevalent across cancer types, with an incidence rate of 83%. Genome-wide bioinformatics analysis of this differential necroptosis sensitivity data in the context of differential gene expression and mutation data across the cell lines identified various factors that correlate with resistance to necroptosis and loss of RIPK3 expression, including oncogenes BRAF and AXL. Inhibition of these oncogenes can rescue the RIPK3 expression loss and regain of necroptosis sensitivity. This genome-wide analysis also identifies that the loss of RIPK3 expression is the primary factor correlating with escape from necroptosis. Thus, we c...Continue Reading

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Feb 14, 2020·Journal of Virology·Siddharth Balachandran, Glenn F Rall
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Datasets Mentioned

BETA
GSE50509

Methods Mentioned

BETA
xenograft
biopsy
xenografts
biopsies
PCR
Electrophoresis

Software Mentioned

GraphPad Prism
ClustVis
cBioportal
Excel
cBio Cancer Genomics Portal
CrossCheck

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