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Mol Cancer Ther. 2016 Oct;15(10):2442-2454. Epub 2016 Jul 25.

Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma.

Author information

1
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. egrimm@mdanderson.org.

Abstract

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. Mol Cancer Ther; 15(10); 2442-54.

PMID:
27458138
PMCID:
PMC5079683
DOI:
10.1158/1535-7163.MCT-15-0963
[Indexed for MEDLINE]
Free PMC Article

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