期刊
CANCER DISCOVERY
卷 8, 期 1, 页码 74-93出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0682
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资金
- Burroughs Wellcome Fund
- National Institutes of Health [1R01CA176111, P01CA168585]
- Ressler Family Foundation
- Melanoma Research Alliance
- Ian Copeland Melanoma Fund
- SWOG/Hope Foundation
- Steven C. Gordon Family Foundation
- Melanoma Research Foundation
- American Skin Association
- American Association for Cancer Research-Amgen, Inc. Fellowship in Clinical/Translational Cancer Research [16-40-11-HUGO]
- Department of Defense Horizon Award
- Dermatology Foundation
- NATIONAL CANCER INSTITUTE [P30CA016042, P01CA168585, R21CA215910, R01CA176111] Funding Source: NIH RePORTER
Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant BRAF(MUT) or NRAS(MUT) melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal-induced pERK rebound upregulated p38-FRA1-JUNB-CDKN1A and downregulated proliferation, but only a robust pERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi addiction across the board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant NRAS(MUT) or atypical BRAF(MUT) melanoma, treatment with a type I RAF inhibitor intensified pERK rebound elicited by MEKi withdrawal, thereby promoting a cell death-predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi addiction. (c) 2017 AACR.
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