期刊
CANCERS
卷 11, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cancers11101480
关键词
oncogene addiction; BRAF-mutant tumors; BRAF and MEK-targeted therapies; phenotype switching; tumor heterogeneity; epigenetic regulation; adaptive drug resistance; histone-modifying enzymes; chromatin regulation; DNA methylation
类别
资金
- NCI [T32-CA009676, R00-CA194163]
- Elsa Pardee Foundation
- V Scholar Grant Award from V Foundation for Cancer Research [V2017-011]
- Department of Defense PRCRP Career Development Award [W81XWH1810427]
- U.S. Department of Defense (DOD) [W81XWH1810427] Funding Source: U.S. Department of Defense (DOD)
About eight percent of all human tumors (including 50% of melanomas) carry gain-of-function mutations in the BRAF oncogene. Mutated BRAF and subsequent hyperactivation of the MAPK signaling pathway has motivated the use of MAPK-targeted therapies for these tumors. Despite great promise, however, MAPK-targeted therapies in BRAF-mutant tumors are limited by the emergence of drug resistance. Mechanisms of resistance include genetic, non-genetic and epigenetic alterations. Epigenetic plasticity, often modulated by histone-modifying enzymes and gene regulation, can influence a tumor cell's BRAF dependency and therefore, response to therapy. In this review, focusing primarily on class 1 BRAF-mutant cells, we will highlight recent work on the contribution of epigenetic mechanisms to inter- and intratumor cell heterogeneity in MAPK-targeted therapy response.
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