MERTK, the macrophage c-mer tyrosine kinase receptor, is a member of the TAM (Tyro3, Axl and MerTK) receptor tyrosine kinase family. It has ligands like Gas6 and Protein S, and is involved in multiple biological processes. MERTK promotes apoptotic cell clearance (efferocytosis) in macrophages and skews macrophage polarization towards a pro-tumor M2-like phenotype [4]. It also participates in signaling pathways such as ERK-TGFβ1 [1], and PI3K/AKT and MAPK/ERK [2].

In disease-related research, MERTK has been shown to play a significant role in various fibrotic diseases. In NASH mice, holo-or myeloid-specific Mertk targeting decreases liver fibrosis, suggesting MERTK promotes liver fibrosis in NASH [1]. In mouse models of liver, kidney, and lung fibrosis, reducing MERTK expression by disrupting the fibrosis-promoting signaling loop reduces organ fibrosis, and pharmacological inhibition of MERTK also alleviates fibrosis [3]. In addition, in EGFR-mutant non-small cell lung cancer, MERTK activation drives osimertinib resistance, and treatment with a MERTK kinase inhibitor resensitizes cells to osimertinib [2].

In conclusion, MERTK is crucial in macrophage-mediated processes like efferocytosis and polarization. Its role in fibrotic diseases and cancer drug resistance has been revealed through studies using gene-targeted mouse models. These findings suggest MERTK could be a potential therapeutic target for treating fibrotic diseases and overcoming drug resistance in certain cancers.

References:

1. Cai, Bishuang, Dongiovanni, Paola, Corey, Kathleen E, Valenti, Luca, Tabas, Ira. 2019. Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. In Cell metabolism, 31, 406-421.e7. doi:10.1016/j.cmet.2019.11.013. https://pubmed.ncbi.nlm.nih.gov/31839486/

2. Yan, Dan, Huelse, Justus M, Kireev, Dmitri, DeRyckere, Deborah, Graham, Douglas K. . MERTK activation drives osimertinib resistance in EGFR-mutant non-small cell lung cancer. In The Journal of clinical investigation, 132, . doi:10.1172/JCI150517. https://pubmed.ncbi.nlm.nih.gov/35708914/

3. Pan, Ziyan, El Sharkway, Rasha, Bayoumi, Ali, George, Jacob, Eslam, Mohammed. 2024. Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease. In Science translational medicine, 16, eadj0133. doi:10.1126/scitranslmed.adj0133. https://pubmed.ncbi.nlm.nih.gov/38569018/

4. Myers, Kayla V, Amend, Sarah R, Pienta, Kenneth J. 2019. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. In Molecular cancer, 18, 94. doi:10.1186/s12943-019-1022-2. https://pubmed.ncbi.nlm.nih.gov/31088471/