MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF^V600E amplification whereas KRAS^G13D amplification promotes EMT-chemoresistance.

ABSTRACT: Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF^V600E or KRAS^G13D to reinstate ERK1/2 signalling. Here we show that BRAF^V600E amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAF^V600E amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57^KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAF^V600E. p57^KIP2 expression is required for loss of BRAF^V600E amplification and reversal o

SUBMITTER: Sale MJ 

PROVIDER: S-EPMC6497655 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature