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.