Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

被引:6
作者
Chen, Wenjing [1 ]
Park, Jong-In [1 ]
机构
[1] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA
关键词
BRAF; MEK; tumor; drug resistance; MUTANT COLORECTAL-CANCER; ACQUIRED-RESISTANCE; MAPK PATHWAY; CONFERS RESISTANCE; IMMUNE MICROENVIRONMENT; METASTATIC MELANOMA; FEEDBACK ACTIVATION; RAF INHIBITION; KINASE; DABRAFENIB;
D O I
10.3390/ijms241914837
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.
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页数:17
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