Format

Send to

Choose Destination
Nat Commun. 2019 Nov 14;10(1):5167. doi: 10.1038/s41467-019-12409-w.

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

Author information

1
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. matthew.sale@babraham.ac.uk.
2
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
3
Oncology R&D, AstraZeneca, One Medimmune Way, Gaithersburg, MD, 20878, USA.
4
Pharmacology and Drug Development Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
5
Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, 02451, USA.
6
Oncology R&D, AstraZeneca, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
7
CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, CB22 3AT, UK.
8
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. simon.cook@babraham.ac.uk.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center