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

https://doi.org/10.1016/j.pharmthera.2020.107577Get rights and content

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.

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

References (318)

  • E.A. Carrera Silva et al.

    T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response

    Immunity

    (2013)
  • S.R. Datta et al.

    Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery

    Cell

    (1997)
  • C. Eken et al.

    Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages

    The Journal of Biological Chemistry

    (2010)
  • W. Fiedler et al.

    Phase I trial of SU14813 in patients with advanced solid malignancies

    Annals of Oncology

    (2011)
  • J. Foran et al.

    A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis

    Clinical Lymphoma, Myeloma & Leukemia

    (2014)
  • G.K. Abou-Alfa et al.

    Cabozantinib in patients with advanced and progressing hepatocellular carcinoma

    The New England Journal of Medicine

    (2018)
  • J. Abraham et al.

    Safety and efficacy of T-DM1 plus neratinib in patients with metastatic HER2-positive breast cancer: NSABP Foundation Trial FB-10

    Journal of Clinical Oncology

    (2019)
  • Y.T. Akalu et al.

    TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy

    Immunological Reviews

    (2017)
  • G. Alasiri et al.

    Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells

    Oncogene

    (2019)
  • F. Alciato et al.

    TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages

    Journal of Leukocyte Biology

    (2010)
  • H.O. Alsaab et al.

    PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome

    Frontiers in Pharmacology

    (2017)
  • D. Alvarado et al.

    Monoclonal antibodies targeting the TAM family of receptor tyrosine kinases [abstract]

  • S. Ammoun et al.

    Axl/Gas6/NFkappaB signalling in schwannoma pathological proliferation, adhesion and survival

    Oncogene

    (2014)
  • O.V. Ancker et al.

    Multikinase inhibitor treatment in thyroid cancer

    International Journal of Molecular Sciences

    (2019)
  • A. Angelillo-Scherrer et al.

    Role of Gas6 in erythropoiesis and anemia in mice

    The Journal of Clinical Investigation

    (2008)
  • A. Angelillo-Scherrer et al.

    Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis

    Nature Medicine

    (2001)
  • M. Atefi et al.

    Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway

    PLoS One

    (2011)
  • J.M. Axten et al.

    Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)

    Journal of Medicinal Chemistry

    (2012)
  • N.M. Ayoub et al.

    Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents

    Oncotargets and Therapy

    (2017)
  • A.A. Azad et al.

    A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naive castration-resistant prostate cancer

    Investigational New Drugs

    (2014)
  • T. Azad et al.

    A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis

    Oncogene

    (2020)
  • S. Barat et al.

    Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma

    Molecular Carcinogenesis

    (2016)
  • M.S. Beg et al.

    A randomized clinical trial of chemotherapy with gemcitabine/cisplatin/nabpaclitaxel with or without the AXL inhibitor bemcentinib (BGB324) for patients with advanced pancreatic cancer

    Journal of Clinical Oncology

    (2019)
  • E.M. Behrens et al.

    The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity

    European Journal of Immunology

    (2003)
  • P. Bergerot et al.

    Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: Rationale and clinical evidence

    Molecular Cancer Therapeutics

    (2019)
  • ElsaLys Biotech

    ELB031 (ANTI-TYRO3 and ANTI-MERTK Antibodies in Oncology). In (Vol. 2019)

    (2018)
  • C. Blank et al.

    PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells

    Cancer Research

    (2004)
  • G.M. Blumenthal et al.

    FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors

    The Oncologist

    (2012)
  • P. Bose et al.

    Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer

    Expert Opinion on Investigational Drugs

    (2009)
  • A. Broniscer et al.

    Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma

    Clinical Cancer Research

    (2013)
  • P. Brown et al.

    Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner

    Leukemia

    (2006)
  • L.A. Byers et al.

    An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance

    Clinical Cancer Research

    (2013)
  • N.B. Caberoy et al.

    Galectin-3 is a new MerTK-specific eat-me signal

    Journal of Cellular Physiology

    (2012)
  • N.B. Caberoy et al.

    Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis

    The EMBO Journal

    (2010)
  • R. Cabezon et al.

    MERTK as negative regulator of human T cell activation

    Journal of Leukocyte Biology

    (2015)
  • M.S. Caetano et al.

    Triple therapy with MerTK and PD1 inhibition plus radiotherapy promotes abscopal antitumor immune responses

    Clinical Cancer Research

    (2019)
  • B. Cai et al.

    Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis

    Cell Metabolism

    (2020)
  • B. Cai et al.

    MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

    Science Signaling

    (2018)
  • B. Cai et al.

    MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

    The Journal of Clinical Investigation

    (2017)
  • B. Cai et al.

    MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

    Proceedings of the National Academy of Sciences of the United States of America

    (2016)
  • Cited by (42)

    View all citing articles on Scopus
    1

    Co-first authors who contributed equally

    2

    Co-senior authors who contributed equally

    View full text