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  • Review Article
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TAM family kinases as therapeutic targets at the interface of cancer and immunity

Nature Reviews Clinical Oncology volume 20, pages 755–779 (2023)Cite this article

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Abstract

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.

Key points

  • Preclinical studies in cell culture and animal models implicate the TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) as promising new therapeutic targets in both cancer cells and the tumour immune microenvironment.

  • TAM RTKs are aberrantly or ectopically expressed in a wide variety of cancers and promote cancer cell survival, metastasis and resistance to both chemotherapy and molecularly targeted agents, and have been associated with poor prognosis.

  • TAM RTKs are also expressed in immune cells in the tumour microenvironment, where they promote expression of anti-inflammatory cytokines, reduce antigen presentation, recruit and/or activate immunosuppressive regulatory T cells and myeloid-derived suppresser cells, interface with immune-checkpoint pathways and, therefore, have a central role in suppression of antitumour immunity.

  • TAM RTKs promote expression of the immune-checkpoint ligands PD-L1 and PD-L2 and have been associated with resistance to immune-checkpoint inhibitors in numerous cancers.

  • The first selective TAM inhibitors have been well-tolerated, with evidence of therapeutic efficacy in early phase clinical trials, and are being tested in combination with a variety of other agents, including chemotherapies, EGFR inhibitors, BCL-2 inhibitors and immune-checkpoint inhibitors.

  • The relevance of individual TAM RTKs as therapeutic targets (particularly in the tumour microenvironment) is probably dependent on several factors, including tumour phenotype and the patient’s immune status, and development of biomarkers to predict and/or monitor therapeutic response will be essential to optimize the application of TAM-targeted agents in patients.

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Fig. 1: TAM structure and activation mechanisms.
Fig. 2: TAM signalling in immune cells.
Fig. 3: Functions of TAM RTKs in the TME.
Fig. 4: TAM RTK signalling and functions in cancer cells.
Fig. 5: TAM-targeted agents in preclinical and clinical development.
Fig. 6: Potential adverse effects of TAM-targeted therapies.

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Acknowledgements

The work of D.D. and D.K.G. is supported by NIH National Cancer Institute (NCI) grants R01 CA 249190–01 and R01 CA 259077–01; and the Emory University Lung Cancer SPORE, P50CA217691. The work of H.S.E. is supported by NIH NCI grant RO1 CA 205398.

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  1. These authors contributed equally: Deborah DeRyckere, Justus M. Huelse.

Authors and Affiliations

  1. Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Deborah DeRyckere, Justus M. Huelse & Douglas K. Graham

  2. Department of Paediatrics, Emory University School of Medicine, Atlanta, GA, USA

    Deborah DeRyckere, Justus M. Huelse & Douglas K. Graham

  3. Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    H. Shelton Earp

  4. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    H. Shelton Earp

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D.D. and J.M.H. researched data for the article and wrote the manuscript. All authors contributed substantially to discussion of the content and/or edited the manuscript before submission.

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H.S.E. and D.K.G. are founders and serve on the Scientific Advisory Board of Meryx, and D.K.G. also serves on the Board of Directors. D.D., H.S.E. and D.K.G. hold equity in Meryx. The key clinical candidate therapeutic being developed by Meryx, MRX-2843, is discussed in this Review.

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Nature Reviews Clinical Oncology thanks K. C. Fuh, who co-reviewed with M. Pereira; R. B. Birge; R. Brekken; and T. Burstyn-Cohen for their contribution to the peer review of this work.

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DeRyckere, D., Huelse, J.M., Earp, H.S. et al. TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nat Rev Clin Oncol 20, 755–779 (2023). https://doi.org/10.1038/s41571-023-00813-7

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