期刊
MOLECULAR CANCER THERAPEUTICS
卷 15, 期 10, 页码 2442-2454出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-0963
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资金
- UT MD Anderson Cancer Center SPORE in Melanoma (NCI) [P50 CA093459]
- Aim at Melanoma Foundation
- Miriam & Jim Mulva Research Funds
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- CCSG grant (NCI) [P30 CA016672]
Melanoma is molecularly and structurally heterogeneous, with some tumor cells existing under hypoxic conditions. Our cell growth assays showed that under controlled hypoxic conditions, BRAF(V600E) melanoma cells rapidly became resistant to vemurafenib. By employing both a three-dimensional (3D) spheroid model and a two-dimensional (2D) hypoxic culture system to model hypoxia in vivo, we identified upregulation of HGF/MET signaling as a major mechanism associated with vemurafenib resistance as compared with 2D standard tissue culture in ambient air. We further confirmed that the upregulation of HGF/MET signaling was evident in drug-resistant melanoma patient tissues and mouse xenografts. Pharmacologic inhibition of the c-Met/Akt pathway restored the sensitivity of melanoma spheroids or 2D hypoxic cultures to vemurafenib. (C) 2016 AACR.
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