TAM receptors (Tyro-3,Axl,and Mertk) Inhibitors
The TAM receptor family, comprising Tyro-3, Axl, and Mertk, represents a critical group of receptor tyrosine kinases (RTKs) that govern essential cellular processes including survival, proliferation, migration, and efferocytosis—the clearance of apoptotic cells. These receptors are activated by their common ligands, Gas6 (Growth Arrest-Specific 6) and Protein S (Pros1), which act as bridges, connecting TAM receptors to phosphatidylserine exposed on apoptotic cells or cellular debris. Upon ligand binding, TAM receptors undergo dimerization and autophosphorylation, initiating downstream signaling cascades such such as the PI3K/Akt, MAPK/ERK, and STAT pathways. These pathways collectively promote cell survival, suppress inflammatory responses, and facilitate immune evasion, making them crucial regulators of tissue homeostasis and immune privilege. Dysregulation of TAM receptor signaling is profoundly implicated in various pathologies. In cancer, overexpression and activation of Axl and Mertk are frequently observed in aggressive malignancies, including lung, breast, ovarian, pancreatic, and glioblastoma, as well as acute myeloid leukemia (AML). They drive tumor cell proliferation, survival, invasion, metastasis, angiogenesis, and contribute significantly to resistance against chemotherapy, radiotherapy, and targeted therapies like EGFR inhibitors.
Tyro-3 also plays a role in cancer progression. Furthermore, Mertk is vital for efferocytosis in macrophages, and its dysfunction can lead to impaired clearance of apoptotic cells, contributing to chronic inflammation and autoimmune diseases such as systemic lupus erythematosus. TAM receptors are also exploited by certain viruses, including Zika and Dengue, for cellular entry and replication, while Mertk mutations are linked to inherited retinal dystrophies. Significant efforts are underway to develop TAM receptor inhibitors, particularly targeting Axl and Mertk in oncology. Many approved or clinical-stage multi-kinase inhibitors, such as cabozantinib, sunitinib, sorafenib, and pazopanib, exhibit some activity against TAM receptors, contributing to their observed efficacy in specific cancers. More selective TAM inhibitors are also emerging. Bemcentinib (BGB324), a selective Axl inhibitor, is currently in Phase II clinical trials for various solid tumors (e.g., lung cancer, melanoma) and AML, often in combination with immunotherapy or chemotherapy.
R428 (BMS-777607) is another selective Axl inhibitor in preclinical and early clinical development. For Mertk, selective inhibitors like UNC2025, UNC2250, and MRX-2843 are in preclinical stages, showing promise in AML and solid tumors, often by enhancing anti-tumor immunity. Anti-Axl antibodies, such as YW327.6S2 and ABBV-151, are also progressing through preclinical and early clinical phases. Currently, no TAM-specific inhibitors are approved, but their inhibition by multi-kinase inhibitors underscores their therapeutic potential. TAM receptor inhibitors are classified by their specific target (selective Axl, Mertk, or Tyro-3 inhibitors; pan-TAM inhibitors; or multi-kinase inhibitors with TAM activity), their chemical nature (small molecules, monoclonal antibodies), and their mechanism (ATP-competitive kinase inhibitors, allosteric inhibitors, or ligand-blocking antibodies). Research tools include R428, UNC2025, and bemcentinib. Challenges include achieving high selectivity for individual TAM receptors over other RTKs due to structural similarities, and managing potential off-target effects and toxicity.
The complex interplay between TAM receptors and the immune system means inhibition can have dual effects, potentially enhancing anti-tumor immunity but also risking autoimmune-like side effects. Combination therapy is a particularly promising strategy, with TAM inhibitors being explored alongside immunotherapies (e.g., checkpoint inhibitors) to overcome immune evasion, and with conventional chemotherapies or targeted therapies to reverse drug resistance in cancer.
