Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.
Nat Commun
; 10(1): 5167, 2019 11 14.
Article
em En
| MEDLINE
| ID: mdl-31727888
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 MCL1BCL-XL ratio; indeed the MCL1BCL-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Apoptose
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Sistema de Sinalização das MAP Quinases
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Proteínas Proto-Oncogênicas B-raf
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Inibidores de Proteínas Quinases
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Terapia de Alvo Molecular
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Melanoma
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido