4.2 TAM Receptors (Tyro3, Axl, and Mer)
TAM receptors, comprising Tyro3 (also called Brt, Dtk, Etk-2, Rek, Rse, Sky, and Tif), Axl (also called Ark, Tyro7, and Ufo), and Mer (also called c-Eyk, Mertk, Nyk, and Tyro12), are a family of receptor tyrosine kinases (RTK) expressed on diverse immune cells and tumor cells. It is composed of an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain [381].
The TAM receptors and their ligands, vitamin K-dependent proteins Gas6 and Protein S, play crucial roles in facilitating the effective phagocytosis of apoptotic cells and membranes within tissues. Additionally, within the immune system, they serve as versatile inhibitors that modulate the innate inflammatory response to pathogens. They also play pivotal roles in regulating processes critical to cancer progression [382]. These receptors are involved in mediating signals that promote tumor growth, survival, invasion, and metastasis, while also contributing significantly to immune evasion mechanisms within the tumor microenvironment. Among the TAM receptors, Axl has emerged as particularly significant due to its association with aggressive tumor phenotypes and resistance to therapies, making it a prime target for therapeutic intervention [383].
In preclinical models, inhibitors specifically targeting Axl have demonstrated efficacy in inhibiting tumor growth and metastasis, as well as in enhancing anti-tumor immune responses by reprogramming the tumor microenvironment towards a more immune-supportive state. In research conducted by Lin et al., both genetic and pharmacological inhibition of AXL in resistant models led to a reduction in cell proliferation, migration, invasion, and tumor growth. These effects were notably enhanced when AXL inhibition was paired with docetaxel treatment [384]. In a study by Taniguchi et al., AXL inhibition decreased the viability of EGFR-mutated lung cancer cells overexpressing AXL treated with osimertinib (EGFR-tyrosine kinase inhibitor), resulting in reduced tumor size and delayed tumor regrowth compared to treatment with osimertinib alone [385]. In a preclinical study, glioblastoma cell lines U118MG and SF126, were treated with  temozolomide (TMZ) and radiation, with and without AXL tyrosine kinase inhibitor (TKI). In the group treated with TZM and radiotherapy alongwith AXL tyrosine kinase inhibitor (R428) showed significantly increased therapeutic effects [386].
Promising preclinical findings have prompted the initiation of clinical trials aimed at evaluating the safety, efficacy, and therapeutic potential of Axl inhibitors, both as monotherapy[ NCT03990454, AXL inhibitor SCL-391] [ NCT02988817, AXL Antibody–drug conjugates Enapotamab vedotin] [ NCT04893551, AXL monoclonal antibodies Tilvestamab (BGB149)] [ NCT02729298, AXL inhibitor Dubermatinib (TP-0903)] , and in combination with other treatment modalities [ NCT02424617, AXL inhibitor Bemcentinib (BGB324) + Erlotinib] [NCT02922777, Bemcentinib + Docetaxel] [NCT03649321, Bemcentinib + + Nab-paclitaxel, gemcitabine, cisplatin] [ NCT03184571, Bemcentinib + Pembrolizumab] [ NCT02488408, Bemcentinib ± Cytarabine or decitabine] [ NCT03255083 , AXL inhibitor DS-1205 + Osimertinib] [ NCT03599518 , AXL inhibitor DS-1205 + Gefitinib] , to validate the preclinical results and to determine whether targeting TAM receptors, especially Axl, can overcome resistance mechanisms and improve outcomes for cancer patients, particularly those with advanced or refractory disease.