TAM inhibitors(Halia Therapeutics)

Tyro-3, Axl, and Mertk (abbreviated TAM receptors or TAMs), have well established functions in efferocytosis, the process by which apoptotic cells are engulfed by phagocytic cells such as macrophages and dendritic cells. In addition to their roles in efferocytosis, TAMs are also pleiotropic immune modulators that dampen inflammation and promote immune resolution and tolerance. Mice lacking one or more of the TAM receptors in various murine models leads to chronic inflammation and in some cases autoimmunity and chronic disease. In recent years, TAMs have emerged as important contributors in cancer, functioning both as oncogenic tyrosine kinases as well as immune modulators. Many recent studies indicate that TAM inhibitors, including monoclonal antibodies, kinase inhibitors, decoy receptors and ligands, and small molecular wedge inhibitors have therapeutic potential in cancer biology and immunotherapy. Here, we report the development and characterization of two type of TAM reporter lines that can be adapted to screen a wide range of TAM inhibitor types. The first involves TAM-IFN-γR1 chimeric CHO lines, where the extracellular domain of human TAM receptors is fused with the transmembrane and intracellular signaling domains of the human IFN-γ receptor chain. The second type of TAM reporter line described is the EGFR-TAM chimeric CHO lines, which involves fusing the extracellular domain of the EGFR receptor with the transmembrane and intracellular tyrosine kinase domains and cytosolic tail of TAM receptors. With minimal adaptation, both lines can be adopted for high throughput screening with immune-oncology applications.

Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumour immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) are potential therapeutic targets in a wide range of cancers. In cancer cells, TAM RTKs activate signalling pathways that promote cell survival, metastasis and resistance to a variety of chemotherapeutic agents and targeted therapies. TAM RTKs also function in innate immune cells, contributing to various mechanisms that suppress antitumour immunity and promote resistance to immune-checkpoint inhibitors. Therefore, TAM antagonists provide an unprecedented opportunity for both direct and immune-mediated therapeutic activity provided by inhibition of a single target, and are likely to be particularly effective when used in combination with other cancer therapies. To exploit this potential, a variety of agents have been designed to selectively target TAM RTKs, many of which have now entered clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians, including an overview of the rationale for therapeutic targeting of TAM RTKs in cancer cells and the tumour immune microenvironment, a description of the current preclinical and clinical experience with TAM inhibitors, and a perspective on strategies for continued development of TAM-targeted agents for oncology applications.