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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Small Molecule Therapeutics

Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma

Lenka Sinik, Katherine A. Minson, John J. Tentler, Jacqueline Carrico, Stacey M. Bagby, William A. Robinson, Rotem Kami, Tal Burstyn-Cohen, S. Gail Eckhardt, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere and Douglas K. Graham
Lenka Sinik
School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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Katherine A. Minson
Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia.
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John J. Tentler
University of Colorado Cancer Center, Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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Jacqueline Carrico
School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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Stacey M. Bagby
University of Colorado Cancer Center, Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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William A. Robinson
University of Colorado Cancer Center, Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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Rotem Kami
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
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Tal Burstyn-Cohen
Institute for Dental Sciences, Faculty of Dental Medicine, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
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S. Gail Eckhardt
Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas.
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Xiaodong Wang
Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Stephen V. Frye
Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
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H. Shelton Earp
UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.Departments of Medicine and Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Deborah DeRyckere
Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia.
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Douglas K. Graham
Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia.
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  • For correspondence: douglas.graham@choa.org
DOI: 10.1158/1535-7163.MCT-18-0456 Published February 2019
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Abstract

Molecularly-targeted agents have improved outcomes for a subset of patients with BRAF-mutated melanoma, but treatment of resistant and BRAF wild-type tumors remains a challenge. The MERTK receptor tyrosine kinase is aberrantly expressed in melanoma and can contribute to oncogenic phenotypes. Here we report the effect of treatment with a MERTK-selective small molecule inhibitor, UNC2025, in preclinical models of melanoma. In melanoma cell lines, treatment with UNC2025 potently inhibited phosphorylation of MERTK and downstream signaling, induced cell death, and decreased colony formation. In patient-derived melanoma xenograft models, treatment with UNC2025 blocked or significantly reduced tumor growth. Importantly, UNC2025 had similar biochemical and functional effects in both BRAF-mutated and BRAF wild-type models and irrespective of NRAS mutational status, implicating MERTK inhibition as a potential therapeutic strategy in tumors that are not amenable to BRAF-targeting and for which there are limited treatment options. In BRAF-mutated cell lines, combined treatment with UNC2025 and the BRAF inhibitor vemurafenib provided effective inhibition of oncogenic signaling through ERK, AKT, and STAT6, increased induction of cell death, and decreased colony-forming potential. Similarly, in NRAS-mutated cell lines, addition of UNC2025 to cobimetinib therapy increased cell death and decreased colony-forming potential. In a BRAF-mutated patient-derived xenograft, treatment with combined UNC2025 and vemurafenib was well-tolerated and significantly decreased tumor growth compared with vemurafenib alone. These data support the use of UNC2025 for treatment of melanoma, irrespective of BRAF or NRAS mutational status, and suggest a role for MERTK and targeted combination therapy in BRAF and NRAS-mutated melanoma.

Footnotes

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

  • Received May 3, 2018.
  • Revision received October 15, 2018.
  • Accepted November 20, 2018.
  • Published first November 27, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (2)
February 2019
Volume 18, Issue 2
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Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma
Lenka Sinik, Katherine A. Minson, John J. Tentler, Jacqueline Carrico, Stacey M. Bagby, William A. Robinson, Rotem Kami, Tal Burstyn-Cohen, S. Gail Eckhardt, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere and Douglas K. Graham
Mol Cancer Ther February 1 2019 (18) (2) 278-288; DOI: 10.1158/1535-7163.MCT-18-0456

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Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma
Lenka Sinik, Katherine A. Minson, John J. Tentler, Jacqueline Carrico, Stacey M. Bagby, William A. Robinson, Rotem Kami, Tal Burstyn-Cohen, S. Gail Eckhardt, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere and Douglas K. Graham
Mol Cancer Ther February 1 2019 (18) (2) 278-288; DOI: 10.1158/1535-7163.MCT-18-0456
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Molecular Cancer Therapeutics
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