Hypoxia-driven mechanism of vemurafenib resistance in melanoma

Yong Qin; Jason Roszik; Chandrani Chattopadhyay; Yuuri Hashimoto; Chengwen Liu; Zachary A. Cooper; Jennifer A. Wargo; Patrick Hwu; Suhendan Ekmekcioglu; Elizabeth A. Grimm

doi:10.1158/1535-7163.MCT-15-0963

Hypoxia-driven mechanism of vemurafenib resistance in melanoma

Yong Qin, Jason Roszik, Chandrani Chattopadhyay, Yuuri Hashimoto, Chengwen Liu, Zachary A. Cooper, Jennifer A. Wargo, Patrick Hwu, Suhendan Ekmekcioglu, Elizabeth A. Grimm

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2442-2454
Number of pages	13
Journal	Molecular cancer therapeutics
Volume	15
Issue number	10
DOIs	https://doi.org/10.1158/1535-7163.MCT-15-0963
State	Published - Oct 2016

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/1535-7163.MCT-15-0963

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title = "Hypoxia-driven mechanism of vemurafenib resistance in melanoma",

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.",

author = "Yong Qin and Jason Roszik and Chandrani Chattopadhyay and Yuuri Hashimoto and Chengwen Liu and Cooper, {Zachary A.} and Wargo, {Jennifer A.} and Patrick Hwu and Suhendan Ekmekcioglu and Grimm, {Elizabeth A.}",

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doi = "10.1158/1535-7163.MCT-15-0963",

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AU - Qin, Yong

AU - Roszik, Jason

AU - Chattopadhyay, Chandrani

AU - Hashimoto, Yuuri

AU - Liu, Chengwen

AU - Cooper, Zachary A.

AU - Wargo, Jennifer A.

AU - Hwu, Patrick

AU - Ekmekcioglu, Suhendan

AU - Grimm, Elizabeth A.

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AB - 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.

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Hypoxia-driven mechanism of vemurafenib resistance in melanoma

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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