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

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 of MEKi resistance. Thus, BRAF(V600E) amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRAS(G13D) amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRAS(G13D) amplification.