Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
Session type: Poster / e-Poster / Silent Theatre session
Theme: Late breaking: Treatment
BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably leads to disease progression. Despite increasing the abundance of the pro-apoptotic BIM and BMF proteins, ERK1/2 pathway inhibition is predominantly cytostatic reflecting residual pro-survival BCL2 family activity.
Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the novel MCL1 inhibitor AZD5991, driving tumour cell death and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-XL inhibitors is typically stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL-XL/BCL2 inhibitors. Death induced by inhibition of ERK1/2-plus-MCL1 is BAK/BAX-dependent and requires BIM and BMF. Finally, AZD5991 delays acquired BRAFi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi-plus-MEKi resistance.
Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.