Format

Send to

Choose Destination
Cancer Discov. 2015 Mar;5(3):274-87. doi: 10.1158/2159-8290.CD-14-0295. Epub 2014 Dec 26.

EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma.

Author information

1
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts. Department of Dermatology, Harvard Medical School, Boston, Massachusetts.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts.
3
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.
4
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
5
Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
6
Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts. MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
8
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts. Department of Dermatology, Harvard Medical School, Boston, Massachusetts. MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. htsao@partners.org.

Abstract

BRAF(V600E) is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EPHA2, a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (EPH) receptors, and (ii) associated with a greater phenotypic dependence on EPHA2. Furthermore, we developed a series of first-in-class EPHA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability, and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof of concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.

SIGNIFICANCE:

In this study, we show that resistance to selective BRAF inhibitors can be mediated by the RTK EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance.

PMID:
25542448
PMCID:
PMC4355085
DOI:
10.1158/2159-8290.CD-14-0295
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center