Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma

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  • Yong Qin
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Jason Roszik
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Chandrani Chattopadhyay
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Yuuri Hashimoto
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Chengwen Liu
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Zachary A. Cooper
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Jennifer A. Wargo
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Patrick Hwu
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Suhendan Ekmekcioglu
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Elizabeth A. Grimm
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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<jats:title>Abstract</jats:title> <jats:p>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. ©2016 AACR.</jats:p>

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