Targeting the TAM receptors in leukemia

• Type of Material: Article
• Authors: Madeline G. Huey, Emory University; Katherine Minson, Emory University; H Shelton Earp, The University of North Carolina at Chapel Hill; Deborah DeRyckere, Emory University; Douglas Graham, Emory University
• Language: English
• Date: 2016-11-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2016 by the authors
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers8110101
• Title of Journal or Parent Work: Cancers
• ISSN: 2072-6694
• Volume: 8
• Issue: 11
• Start Page: 101
• End Page: 101
• Grant/Funding Information: This work was supported in part by the Atlanta Pediatric Scholars program and research grant K12HD072245 (KM).
• Keywords: tyrosine kinase inhibitor; MERTK; resistance; TYRO3; signaling pathways; multiple myeloma; AXL; hematopoiesis; leukemia; Gas6
• Research Categories: Health Sciences, General; Health Sciences, Oncology

Abstract

Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B-and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.