Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
| Autor: | Emma Minihane, Jonathan R. Dry, Simon J. Cook, Mario Aladren Vicente, Matthew J. Sale, Noel R. Monks, Paul D Smith, Aleksandra Markovets, Lisa Drew, Duncan I. Jodrell, Frances M. Richards, Theresa Proia, Courtney L. Andersen, Emma J. Davies, Vikki Flemington, Eiko Ozono, Rebecca Gilley, Kevin Schifferli |
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| Přispěvatelé: | Richards, Frances M. [0000-0001-7947-7853], Andersen, Courtney L. [0000-0003-2064-2273], Jodrell, Duncan I. [0000-0001-9360-1670], Smith, Paul D. [0000-0002-2812-5978], Cook, Simon J. [0000-0001-9087-1616], Apollo - University of Cambridge Repository, Richards, Frances M [0000-0001-7947-7853], Andersen, Courtney L [0000-0003-2064-2273], Jodrell, Duncan I [0000-0001-9360-1670], Smith, Paul D [0000-0002-2812-5978], Cook, Simon J [0000-0001-9087-1616] |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
45/41 General Physics and Astronomy Apoptosis Drug resistance 13/2 chemistry.chemical_compound Mice 0302 clinical medicine hemic and lymphatic diseases MCL1 Molecular Targeted Therapy lcsh:Science Melanoma Multidisciplinary 3. Good health 13/31 Cancer therapeutic resistance 631/67/1059/602 030220 oncology & carcinogenesis 38/39 Growth inhibition biological phenomena cell phenomena and immunity Cell signalling Proto-Oncogene Proteins B-raf Cell death Programmed cell death Macrocyclic Compounds 631/80/82 Cell Survival MAP Kinase Signaling System Science bcl-X Protein 631/80/86 13/106 13/109 General Biochemistry Genetics and Molecular Biology Article 38 96/95 03 medical and health sciences Therapeutic index 14/34 Targeted therapies In vivo Cell Line Tumor medicine Animals Humans Protein Kinase Inhibitors neoplasms 42 45 business.industry Comment General Chemistry medicine.disease digestive system diseases 030104 developmental biology chemistry Drug Resistance Neoplasm Cancer research Myeloid Cell Leukemia Sequence 1 Protein lcsh:Q business |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-19 (2019) |
| ISSN: | 2041-1723 |
| Popis: | 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. BRAF or MEK1/2 inhibitors are cytostatic in melanoma and the surviving cells develop drug resistance. This study shows that the pro-survival pool is biased towards MCL1 in melanoma so that BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, improving tumour growth inhibition. |
| Databáze: | OpenAIRE |
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