Targeting the TAM Receptors in Leukemia

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.

The effects of vitamin K1 and vitamin K2 on the proliferation, cytokine production and regulatory T‐cell frequency in peripheral blood mononuclear cells of paediatric atopic dermatitis patients

“…Gas6 is a plasma vitamin K‐dependent protein that plays an important immunoregulatory role in various cells by interacting with the three receptors of TAM (Tyro3, Axl and Mertk) . However, lymphocytes do not express TAM receptors; thus, the GAS6 receptors do not seem to be related to the main mechanism underlying the effects of VK 2 .…”

RNAi screening of the tyrosine kinome in primary patient samples of acute myeloid leukemia

“…Not much is known about the significance of TYRO3 in AML, although it has been shown to be upregulated in AML 21 and targeting similar family members is an active area of investigation in leukemia. 22 We recently presented some data on the significance of TYRO3 in AML, 23 although we are conducting more research to uncover its full significance.…”

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

“…As a result, TAM receptors seem an attractive target for cancer therapy, not in the least to overcome therapy resistance. Many small molecule inhibitors have been developed, which are usually reactive to all three TAM receptors [15]. Currently, AXL inhibitors are in clinical testing for NSCLC and pan-TAM inhibitors are in clinical testing for the treatment of metastasized solid tumors [8,16].…”

“…In addition, many inhibitors are currently in the preclinical phase where they show anti-tumor activity (reviewed in [8]). Finally, MERTK is frequently overexpressed in leukemias, including T-ALL [15,17]. Mouse studies show promising results where MERTK inhibition favors tumor regression [18].…”