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.
Highlights
Leukemia and other lymphoid neoplasms, make up the fifth most common cancer type in the United States, with an estimated 162,020 new cases and approximately 56,630 deaths due to the disease per year [1]
The TAM receptor tyrosine kinases (RTKs) ligand Gas6, which has higher affinity for AXL relative to the other TAM RTKs [56], has been identified as a poor prognostic factor in acute myeloid leukemia (AML) [10], Gas6 is expressed at low levels in AML cells but is produced in the bone marrow stroma [9]. These observations suggest a role for paracrine signaling between leukemia cells and the bone marrow microenvironment such that together, Gas6 and AXL contribute to tumor cell survival
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
Summary
Leukemia and other lymphoid neoplasms, make up the fifth most common cancer type in the United States, with an estimated 162,020 new cases and approximately 56,630 deaths due to the disease per year [1]. New targets and therapies for leukemia treatment are needed to provide safer, more effective options for patients with leukemia and this need is urgent for patients with AML. These therapies will be efficacious alone and extremely potent in combination with other therapeutics. AXL and its ligand Gas have been identified as predictors of poor outcome in AML [9,10] These and other data identify TAM RTKs as potential therapeutic targets in numerous hematopoietic malignancies. As TYRO3, AXL, and MERTK are attractive therapeutic targets in leukemia, we will discuss recent advances toward introduction of small molecule inhibitors of MERTK and AXL into the clinic
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