Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31727888.
- Also identified by DOI 10.1038/s41467-019-12409-w and PMC identifier 6856071.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>L</sub> 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<sub>L</sub> inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X<sub>L</sub> ratio; indeed the MCL1:BCL-X<sub>L</sub> ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X<sub>L</sub> 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.
Medical subject headings
- Apoptosis
- MAP Kinase Signaling System
- Melanoma
- Molecular Targeted Therapy
- Myeloid Cell Leukemia Sequence 1 Protein
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins B-raf