Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition.

ABSTRACT: Although targeted MAPK pathway inhibition has achieved remarkable patient responses in many cancers, the development of resistance has remained a critical challenge. Adaptive tumor response underlies the drug resistance. Furthermore, such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies. Here, we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted MAPK signaling inhibition in melanoma leads to a profound remodeling of the pTyr proteome. Intriguingly, altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found an accumulation of intracellular cholesterol in melanoma cells (with BRAF^V600E mutati

SUBMITTER: Wang XD 

PROVIDER: S-EPMC8905657 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature