title: EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts. Department of Dermatology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Benchun
authors.initials: B
authors.lastname: Miao
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts. Department of Dermatology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts. Department of Dermatology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts. MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: 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.
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D036104:Receptor, EphA2; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases