Dataset Information

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.

SUBMITTER: Huey MG

PROVIDER: S-EPMC5126761 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Targeting the TAM Receptors in Leukemia.

Huey Madeline G MG Minson Katherine A KA Earp H Shelton HS DeRyckere Deborah D Graham Douglas K DK

Cancers 20161108 11

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 megakaryopo ...[more]

PMID: 27834816

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Project description:Lung cancer remains a leading cause of cancer death worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Immune checkpoint inhibitors (CPIs), including those targeting programmed cell death protein-1 and its ligand (PD-1/PD-L1), have revolutionized the treatment landscape for various cancers. Notably, PD-1/PD-L1 inhibitor-based regimens now form the standard first-line therapy for metastatic NSCLC, substantially improving patients' overall survival. Despite the progress made using CPI-based therapies in advanced NSCLC, most patients experience disease progression after an initial response due to resistance. Given the currently limited therapeutic options available for second-line and beyond settings in NSCLC, new treatment approaches are needed to improve long-term survival in these patients. Thus, CPI resistance is an emerging concept in cancer treatment and an active area of clinical research.Among the key mechanisms of CPI resistance is the immunosuppressive tumor microenvironment (TME). Effective CPI therapy is based on shifting immune responses against cancer cells, therefore, manipulating the immunosuppressive TME comprises an important strategy to combat CPI resistance. Several aspects of the TME can contribute to treatment resistance in NSCLC, including through the activation of Tyro3, Axl, MerTK (TAM) receptors which are essential pleiotropic regulators of immune homeostasis. Their roles include negatively modulating the immune response, therefore ectopic expression of TAM receptors in the context of cancer can contribute to the immunosuppressive, protumorigenic TME. Furthermore, TAM receptors represent important candidates to simultaneously target both tumor cells and immune cells in the TME. Clinical development of TAM receptor inhibitors (TAM RIs) is increasingly focused on their ability to rescue the antitumor immune response, thereby shifting the immunosuppressive TME to an immunostimulatory TME. There is a strong biological rationale for combining TAM RIs with a CPI to overcome resistance and improve long-term clinical responses in NSCLC. Combinatorial clinical trials of TAM RIs with CPIs are underway with encouraging preliminary results. This review outlines the key mechanisms of CPI resistance, including the role of the immunosuppressive TME, and discusses the rationale for targeting TAM receptors as a novel, promising therapeutic strategy to overcome CPI resistance in NSCLC.

Dataset Information

Targeting the TAM Receptors in Leukemia.

Publications

Targeting the TAM Receptors in Leukemia.

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