Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.

ABSTRACT: BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X_L expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-X_L inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X_L ratio; indeed the MCL1:BCL-X_L ratio is predictive of ERK

SUBMITTER: Sale MJ 

PROVIDER: S-EPMC6856071 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature