MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system

• Authors: Justus M Huelse, Emory University; Diana Fridlyand, Emory University; Shelton Earp, University of North Carolina; Deborah DeRyckere, Emory University; Douglas Graham, Emory University
• Journal Title: PHARMACOLOGY & THERAPEUTICS
• Volume: Volume 213
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD | 2020-09-01, Pages 107577-107577
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.pharmthera.2020.107577
• Subjects: Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; MERTK; neoplasia; anti-tumor immunity; preclinical agents; clinical trials; SMALL-MOLECULE INHIBITOR; PHASE-I TRIAL; MYELOID-LEUKEMIA CELLS; ADVANCED SOLID TUMORS; ARREST-SPECIFIC GENE; C-MET INHIBITOR; LUNG-CANCER; APOPTOTIC CELLS; BREAST-CANCER; TAM RECEPTORS

Abstract

The receptor tyrosine kinase MERTK is aberrantly expressed in numerous human malignancies, and is a novel target in cancer therapeutics. Physiologic roles of MERTK include regulation of tissue homeostasis and repair, innate immune control, and platelet aggregation. However, aberrant expression in a wide range of liquid and solid malignancies promotes neoplasia via growth factor independence, cell cycle progression, proliferation and tumor growth, resistance to apoptosis, and promotion of tumor metastases. Additionally, MERTK signaling contributes to an immunosuppressive tumor microenvironment via induction of an anti-inflammatory cytokine profile and regulation of the PD-1 axis, as well as regulation of macrophage, myeloid-derived suppressor cell, natural killer cell and T cell functions. Various MERTK-directed therapies are in preclinical development, and clinical trials are underway. In this review we discuss MERTK inhibition as an emerging strategy for cancer therapy, focusing on MERTK expression and function in neoplasia and its role in mediating resistance to cytotoxic and targeted therapies as well as in suppressing anti-tumor immunity. Additionally, we review preclinical and clinical pharmacological strategies to target MERTK.