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

Matthew J. Sale (), Emma Minihane, Noel R. Monks, Rebecca Gilley, Frances M. Richards, Kevin P. Schifferli, Courtney L. Andersen, Emma J. Davies, Mario Aladren Vicente, Eiko Ozono, Aleksandra Markovets, Jonathan R. Dry, Lisa Drew, Vikki Flemington, Theresa Proia, Duncan I. Jodrell, Paul D. Smith and Simon J. Cook ()
Additional contact information
Matthew J. Sale: Babraham Research Campus
Emma Minihane: Babraham Research Campus
Noel R. Monks: Oncology R&D, AstraZeneca
Rebecca Gilley: Babraham Research Campus
Frances M. Richards: University of Cambridge, Li Ka Shing Centre
Kevin P. Schifferli: Oncology R&D, AstraZeneca
Courtney L. Andersen: Oncology R&D, AstraZeneca
Emma J. Davies: University of Cambridge, Li Ka Shing Centre
Mario Aladren Vicente: Babraham Research Campus
Eiko Ozono: Babraham Research Campus
Aleksandra Markovets: Oncology R&D, AstraZeneca
Jonathan R. Dry: Oncology R&D, AstraZeneca
Lisa Drew: Oncology R&D, AstraZeneca
Vikki Flemington: University of Cambridge, Li Ka Shing Centre
Theresa Proia: Oncology R&D, AstraZeneca
Duncan I. Jodrell: University of Cambridge, Li Ka Shing Centre
Paul D. Smith: University of Cambridge, Li Ka Shing Centre
Simon J. Cook: Babraham Research Campus

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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-XL 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-XL inhibitors is 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 BCL2/BCL-w/BCL-XL inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

Date: 2019
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DOI: 10.1038/s41467-019-12409-w

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