Therapeutic targeting of the functionally elusive TAM receptor family

Abstract

The TAM receptor family of TYRO3, AXL and MERTK regulates tissue and immune homeostasis. Aberrant TAM receptor signalling has been linked to a range of diseases, including cancer, fibrosis and viral infections. Specifically, the dysregulation of TAM receptors can enhance tumour growth and metastasis due to their involvement in multiple oncogenic pathways. For example, TAM receptors have been implicated in the epithelial-mesenchymal transition, maintaining the stem cell phenotype, immune modulation, proliferation, angiogenesis and resistance to conventional and targeted therapies. Therapeutically, multiple TAM receptor inhibitors are in preclinical and clinical development for cancers and other indications, with those targeting AXL being the most clinically advanced. Although there has been notable clinical advancement in recent years, challenges persist. This Review aims to provide both biological and clinical insights into the current therapeutic landscape of TAM receptor inhibitors, and evaluates their potential for the treatment of cancer and non-malignant diseases.

Fig. 1 |. TAM receptors and their interacting ligands.

TAM receptors are activated by growth arrest-specific protein 6 (GAS6) and vitamin K-dependent protein S1 (PROS1). The biological consequences of GAS6 and PROS1 signalling are listed. The three TAM receptors AXL, MERTK and TYRO3 interact with their ligands in the form of a dimer. Ligands also form dimers and bind to the receptor amino-terminal immunoglobulin-like domains, which are connected to two fibronectin type III domains. The intracellular kinase domains of all three TAM family members share close sequence homology and have autophosphorylation sites throughout the domain. Enzyme-induced cleavage can occur in proximity to the cell membrane to release soluble forms of the TAM receptors.

Fig. 2 |. TAM receptor signalling maintains physiological homeostasis.

a, Viral entry into host cells can occur through the binding of growth arrest-specific protein 6 (GAS6) or vitamin K-dependent protein S1 (PROS1), which are expressed on phosphatidylserine-presenting membranes as part of the viral envelope. Upon receptor–ligand binding and activation, TAM receptors suppress the immune response by engaging in crosstalk with the interferon-α/β receptor (IFNAR)–STAT pathway. This pathway leads to SOCS1- and SOCS3-mediated inhibition of Toll-like receptor (TLR) signalling and suppression of inflammatory responses, helping the virus evade immune surveillance. b, TAM receptors, particularly MERTK, are required for the phagocytic clearance of apoptotic cells and cellular debris. MERTK is expressed by phagocytes such as macrophages and retinal pigment epithelium (RPE) cells, which recognize and engulf GAS6-expressing and PROS1-expressing apoptotic cells and cellular debris such as photoreceptor outer segments. Phagocytosis restores tissue homeostasis and avoids inflammatory responses and autoimmune disease. c, GAS6-mediated and PROS1-mediated TAM receptor activation is essential for blood vessel growth and vascular integrity. Crosstalk between TAM receptors and VEGF receptor signalling facilitates downstream phosphatidylinositol 3-kinase (PI3K)–PIP₃ pathways. Crosstalk between TAM receptors and receptor tyrosine kinase signalling can also occur.

Fig. 3 |. The role of TAM receptor signalling in cancer and the action of specific inhibitors.

A subset of the key oncogenic signalling pathways and biological outcomes driven by the TAM receptors AXL, TYRO3 and MERTK in facilitating cancer progression. When activated by growth arrest-specific protein 6 (GAS6) and vitamin K-dependent protein S1 (PROS1), AXL engages the SRC protein, which recruits GRB2 and SOS to facilitate the Ras–Raf–MEK–ERK signalling pathway. TYRO3 signals through the SRC and phosphatidylinositol 3-kinase (PI3K)–AKT pathways, promoting the activation of downstream molecules such as mTORC1 and NRF2. MERTK activation channels into various signalling pathways, notably PI3K–AKT, JAK–STAT3/5/6 and SRC. TAM receptors can recruit and activate overlapping downstream signalling pathways. However, distinct temporal and spatial regulation can produce varied biological outcomes. Upon activation, TAM receptors enhance cancer cell proliferation, tumour cell survival and metastasis. They also stimulate angiogenesis and contribute to immune suppression. Two categories of TAM inhibitors are illustrated. The first includes molecules such as crizotinib, sunitinib and bemcentinib, which directly target the kinase domain of the TAM receptors, inhibiting kinase activity. The second category, represented by agents such as tilvestamab, mipasetamab uzopritine and batiraxcept, disrupts receptor–ligand binding.

Fig. 4 |. GAS6-mediated TAM receptor signalling promotes fibrosis in response to tissue injury.

Chronic inflammation in stromal tissues promotes TAM receptor activity within the tissue microenvironment in different cell types such as epithelial cells, fibroblasts and pro-inflammatory macrophages. This triggers a sequence of biological events leading to tissue fibrosis. Elevated TAM receptor activation boosts the secretion of pro-inflammatory cytokines and promotes macrophage infiltration, leading to epithelial–mesenchymal transition and the deposition of fibrotic matrix (1). Stromal cell-derived growth arrest-specific protein 6 (GAS6) is upregulated in response to tissue injury, resulting in TAM receptor activation on cells within the extracellular matrix (ECM). TAM receptor activation facilitates the generation and transformation of myofibroblasts, which further contribute to the deposition of ECM and fibrosis. Additionally, TAM receptor signalling modulates the activity of immune cells, and promotes the release of pro-fibrotic cytokines (2). TAM receptors promote TGFβ signalling, a critical mediator of fibrosis. The molecular interplay between TAM receptors and TGFβ signalling results in the upregulation of pro-fibrotic factors, such as SLUG, α-smooth muscle actin (α-SMA) and type I collagen COL1A1(3).