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MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents.
McDaniel, Nellie K; Cummings, Christopher T; Iida, Mari; Hülse, Justus; Pearson, Hannah E; Vasileiadi, Eleana; Parker, Rebecca E; Orbuch, Rachel A; Ondracek, Olivia J; Welke, Noah B; Kang, Grace H; Davies, Kurtis D; Wang, Xiaodong; Frye, Stephen V; Earp, H Shelton; Harari, Paul M; Kimple, Randall J; DeRyckere, Deborah; Graham, Douglas K; Wheeler, Deric L.
Afiliación
  • McDaniel NK; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Cummings CT; Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • Iida M; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Hülse J; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.
  • Pearson HE; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Vasileiadi E; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.
  • Parker RE; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.
  • Orbuch RA; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Ondracek OJ; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Welke NB; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Kang GH; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Davies KD; Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • Wang X; 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.
  • Frye SV; 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.
  • Earp HS; Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
  • Harari PM; Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
  • Kimple RJ; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • DeRyckere D; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Graham DK; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • Wheeler DL; Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.
Mol Cancer Ther ; 17(11): 2297-2308, 2018 11.
Article en En | MEDLINE | ID: mdl-30093568
The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Proteínas Tirosina Quinasas Receptoras / Resistencia a Antineoplásicos / Terapia Molecular Dirigida / Tirosina Quinasa c-Mer Límite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Proteínas Tirosina Quinasas Receptoras / Resistencia a Antineoplásicos / Terapia Molecular Dirigida / Tirosina Quinasa c-Mer Límite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos