The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice.
Keywords: Axl; Gas6; Mertk; Tyro3; immune evasion; protein S; tumor microenvironment.
Conflict of interest statement
The authors declare no conflict of interest.
Requirement of Gamma-Carboxyglutamic Acid Modification and Phosphatidylserine Binding for the Activation of Tyro3, Axl, and Mertk Receptors by Growth Arrest-Specific 6.Front Immunol. 2017 Nov 10;8:1521. doi: 10.3389/fimmu.2017.01521. eCollection 2017. Front Immunol. 2017. PMID: 29176978 Free PMC article.
Targeting the TAM Receptors in Leukemia.Cancers (Basel). 2016 Nov 8;8(11):101. doi: 10.3390/cancers8110101. Cancers (Basel). 2016. PMID: 27834816 Free PMC article. Review.
The role of TAM family receptors and ligands in the nervous system: From development to pathobiology.Pharmacol Ther. 2018 Aug;188:97-117. doi: 10.1016/j.pharmthera.2018.03.002. Epub 2018 Mar 4. Pharmacol Ther. 2018. PMID: 29514053 Free PMC article. Review.
Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity.Sci Rep. 2017 Mar 8;7:43908. doi: 10.1038/srep43908. Sci Rep. 2017. PMID: 28272423 Free PMC article.
TAM receptors, Phosphatidylserine, inflammation, and Cancer.Cell Commun Signal. 2019 Nov 27;17(1):156. doi: 10.1186/s12964-019-0461-0. Cell Commun Signal. 2019. PMID: 31775787 Free PMC article. Review.
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