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


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Matthew J. Sale1,Emma Minihane1,Noel R. Monks2,Rebecca Gilley1,Frances M. Richards3,Kevin P. Schifferli2,Courtney L. Andersen2,Emma J. Davies2,Mario Aladren Vicente4,Eiko Ozono1,Aleksandra Markovets2,Lisa Drew2,Vikki Flemington2,Theresa Proia2,Duncan I. Jodrell5,Paul D. Smith2,Simon J. Cook1
1Babraham Institute,2AstraZeneca,3Cancer Research UK,4CRUK Therapeutic Discovery Laboratories,5CRUK

Abstract

Background

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.

Method

Results

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.

Conclusion

Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.