دورية أكاديمية
Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
| العنوان: | Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors |
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| المؤلفون: | Sale, Matthew J., Minihane, Emma, Monks, Noel R., Gilley, Rebecca, Richards, Frances M., Schifferli, Kevin P., Andersen, Courtney L., Davies, Emma J., Vicente, Mario Aladren, Ozono, Eiko, Markovets, Aleksandra, Dry, Jonathan R., Drew, Lisa, Flemington, Vikki, Proia, Theresa, Jodrell, Duncan I., Smith, Paul D., Cook, Simon J. |
| المساهمون: | Cancer Research UK, RCUK | Biotechnology and Biological Sciences Research Council, AstraZeneca |
| المصدر: | Nature Communications ; volume 10, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary |
| الوصف: | 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 L 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 L inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X L ratio; indeed the MCL1:BCL-X L ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X L 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-019-12409-w |
| الإتاحة: | https://doi.org/10.1038/s41467-019-12409-wTest https://www.nature.com/articles/s41467-019-12409-w.pdfTest https://www.nature.com/articles/s41467-019-12409-wTest |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.9C3B08F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-019-12409-w |
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