MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system
Section snippets
Introduction to MERTK
MERTK (myeloid-epithelial-reproductive tyrosine kinase) is a receptor tyrosine kinase (RTK) that is frequently abnormally expressed in a broad range of human cancers (Graham, DeRyckere, Davies, & Earp, 2014; Linger, Keating, Earp, & Graham, 2008). Although this RTK, like others, can promote tumor cell proliferation to some extent, MERTK primarily lends tumor cells crucial survival advantages while promoting invasion, migration and metastasis, drug resistance and, in the innate immune system,
Physiologic MERTK functions
Physiologically, MERTK is centrally involved in regulating tissue homeostasis and repair as well as innate immune control. In many cases these functions are linked to MERTK’s role in mediating efferocytosis by monocyte-derived immune cells, such as macrophages, and by epithelial cells.
MERTK expression in human malignancy
MERTK is aberrantly expressed in a variety of malignancies including acute myeloid leukemia (AML) (Lee-Sherick et al., 2013), acute lymphoblastic leukemia (ALL) (Graham et al., 1994; Graham et al., 2006; Linger et al., 2013), lymphoma (Shi et al., 2018), lung cancer (Linger et al., 2013), astrocytoma (Keating et al., 2010), breast cancer (Nguyen et al., 2014), gastric cancer (Yi et al., 2017), melanoma (Schlegel et al., 2013), rhabdomyosarcoma (Khan et al., 1999), prostate cancer (Y. M. Wu,
MERTK in anti-tumor immunity
MERTK signaling controls innate immunity as part of a regulatory feedback mechanism that limits the extent of inflammatory responses. Thus, under physiologic conditions, MERTK prevents chronic inflammation and auto-immunity. However, in the context of cancer, MERTK can be subverted and contributes to an immune-suppressive microenvironment that promotes cancer growth and progression (Fig. 3). Therefore, inhibiting MERTK signaling in the tumor microenvironment represents a potential
Agents in preclinical development
Inhibitors that target MERTK, AXL and/or TYRO3 have been developed, including both biologic agents and small molecules. Biologic agents include Mer590, a monoclonal antibody directed against the extracellular domain of human MERTK that inhibited MERTK phosphorylation and downstream signaling, reduced colony formation, and increased sensitivity to treatment with carboplatin chemotherapy in NSCLC cultures (Cummings et al., 2014). ELB031, a monoclonal antibody that targets TYRO3 and MERTK, is
Summary and perspectives
MERTK is an emerging target for cancer therapy. MERTK is aberrantly expressed in a wide variety of malignancies and has numerous roles in oncogenesis. MERTK promotes growth factor independence, survival signaling, and tumor cell motility, leading to oncogenic transformation, enhanced tumor growth, therapeutic resistance, and metastasis. In addition, MERTK is expressed in the innate immune system, where it can be subverted to suppress anti-tumor immunity. Thus, therapeutic strategies targeting
Declaration of Competing Interest
Diana Fridlyand – The author declares that there are no conflicts of interest
Justus Huelse – The author declares that there are no conflicts of interest
Shelton Earp – The author holds equity in Meryx incorporated and is on the Meryx board of directors
Deborah DeRyckere – The author holds equity in Meryx incorporated
Douglas K. Graham – The author holds equity in Meryx incorporated and is on the Meryx board of directors
Acknowledgements
This work was supported by the National Cancer Institute of the National Institutes of Health under Award Number P50CA217691 (DKG, DD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number T32HL 139443 (DMF). The content is solely the responsibility of the authors and
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