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Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype

Kim H.T. Paraiso, Meghna Das Thakur, Bin Fang, John M. Koomen, Inna V. Fedorenko, Jobin K. John, Hensin Tsao, Keith T. Flaherty, Vernon K. Sondak, Jane L. Messina, Elena B. Pasquale, Alejandro Villagra, Uma N. Rao, John M. Kirkwood, Friedegund Meier, Sarah Sloot, Geoffrey T. Gibney, Darrin Stuart, Hussein Tawbi and Keiran S.M. Smalley
Kim H.T. Paraiso
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Meghna Das Thakur
2Novartis Institute for Biomedical Research, Emeryville, California.
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Bin Fang
3The Proteomics Core, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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John M. Koomen
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Inna V. Fedorenko
4Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Jobin K. John
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Hensin Tsao
5Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
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Keith T. Flaherty
6Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Vernon K. Sondak
7Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Jane L. Messina
7Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
8Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Elena B. Pasquale
9Sanford-Burnham Medical Research Institute, La Jolla, California.
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Alejandro Villagra
10Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Uma N. Rao
11Department of Medicine, Division of Hematology/Oncology, School of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
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John M. Kirkwood
11Department of Medicine, Division of Hematology/Oncology, School of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
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Friedegund Meier
12Department of Dermato-Oncology, University of Tuebingen, Tuebingen, Germany.
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Sarah Sloot
7Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Geoffrey T. Gibney
7Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Darrin Stuart
2Novartis Institute for Biomedical Research, Emeryville, California.
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Hussein Tawbi
11Department of Medicine, Division of Hematology/Oncology, School of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
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Keiran S.M. Smalley
4Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
7Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • For correspondence: keiran.smalley@moffitt.org
DOI: 10.1158/2159-8290.CD-14-0293 Published March 2015
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Abstract

Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.

Significance: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. Cancer Discov; 5(3); 264–73. ©2014 AACR.

See related article by Miao et al., p. 274

This article is highlighted in the In This Issue feature, p. 213

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received March 20, 2014.
  • Revision received December 17, 2014.
  • Accepted December 19, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Discovery: 5 (3)
March 2015
Volume 5, Issue 3
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Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype
Kim H.T. Paraiso, Meghna Das Thakur, Bin Fang, John M. Koomen, Inna V. Fedorenko, Jobin K. John, Hensin Tsao, Keith T. Flaherty, Vernon K. Sondak, Jane L. Messina, Elena B. Pasquale, Alejandro Villagra, Uma N. Rao, John M. Kirkwood, Friedegund Meier, Sarah Sloot, Geoffrey T. Gibney, Darrin Stuart, Hussein Tawbi and Keiran S.M. Smalley
Cancer Discov March 1 2015 (5) (3) 264-273; DOI: 10.1158/2159-8290.CD-14-0293

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Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype
Kim H.T. Paraiso, Meghna Das Thakur, Bin Fang, John M. Koomen, Inna V. Fedorenko, Jobin K. John, Hensin Tsao, Keith T. Flaherty, Vernon K. Sondak, Jane L. Messina, Elena B. Pasquale, Alejandro Villagra, Uma N. Rao, John M. Kirkwood, Friedegund Meier, Sarah Sloot, Geoffrey T. Gibney, Darrin Stuart, Hussein Tawbi and Keiran S.M. Smalley
Cancer Discov March 1 2015 (5) (3) 264-273; DOI: 10.1158/2159-8290.CD-14-0293
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