MERTK Gene Editing    

Mer tyrosine kinase (MERTK) is a member of the tumor-associated macrophage (TAM) family of receptor tyrosine kinases (RTKs), which also includes Axl and Tyro3. These 3 RTKs are overexpressed across many human tumors; in neoplastic cells, each can signal through canonical survival, motility, and invasion pathways. Although this RTK, like others, can promote tumor cell proliferation to a certain extent, MERTK mainly lends tumor cells crucial survival advantages while promoting migration, invasion and metastasis, drug resistance and, in the innate immune system, suppressing anti-tumor immunity. Besides, MERTK overexpression can be transforming in some cases: transgenic expression in the hematopoietic lineage induces lymphoblastic leukemia or lymphoma in mice and retroviral transduction of the chicken orthologue v-eyk is related to cancer development in chickens. Therefore, MERTK is an attractive potential target for cancer therapy and clinical trials targeting MERTK have now been launched.

MERTK in Cancer Cells

MERTK is aberrantly expressed in a variety of malignancies including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma, lung cancer, astrocytoma, gastric cancer, melanoma, breast cancer, rhabdomyosarcoma, colon cancer, prostate cancer, glioblastoma multiforme (GBM), head and neck squamous cell cancer (HNSCC), schwannoma and neuroblastoma, implicating MERTK as a potential therapeutic target. MERTK expression is related to growth factor independence and decreased apoptosis, especially in stressful conditions with limited nutrients or hypoxia.

Figure 1. MERTK regulating hallmarks of cancer. (Huelse J, et al., 2020)

Ligand binding results in homodimerization and autophosphorylation of MERTK and MERTK activation leads to signaling via canonical oncogenic pathways such as PI3K/AKT, MEK/ERK, and JAK/STAT, resulting in cell growth and proliferation, evasion of apoptosis, cell cycle progression, and tumor growth. RAS activation downstream of MERTK promotes gene transcription through the RAS/RAF/MEK/ERK pathway, resulting in cell proliferation, survival, and metastases. Stimulation with GAS6 ligand resulted in the activation of ERK1/2 and shRNA mediated Mertk knockdown led to decreased ERK activation in B-ALL, T-ALL, AML, NSCLC, astrocytoma and melanoma cell lines. MERTK activation also led to pro-survival signaling through regulation of PI3K/AKT in B-ALL, NSCLC, melanoma, and astrocytoma cell lines. Moreover, PI3K activation is related to MERTK activation in NIH 3T3 fibroblasts and AKT has been implicated downstream of PI3K in macrophage activation and polarization, cell growth and proliferation, and cell survival.

MERTK as A Therapeutic Target in Cancer

Inhibitors that target MERTK, TYRO3 and/or AXL have been developed, including biologic agents and small molecules. Biologic agents include Mer590, a monoclonal antibody directed against the extracellular domain of human MERTK, which inhibited MERTK phosphorylation and downstream signaling, reduced colony formation, and increased sensitivity to treatment with carboplatin chemotherapy in NSCLC cultures. In addition, with the recent focus on MERTK as an immune-oncologic target, many companies have reported novel MERTK-targeted antibodies in the early stages of development. In in vivo models of colon and breast cancers, tumor volume was significantly decreased in response to treatment with anti-MERTK antibody, both as a single agent and in combination with immune checkpoint inhibitors targeting the PD-1 axis. Interestingly, in some cases, these antibodies inhibit MERTK-dependent immune functions, but not MERTK kinase. This uncoupling of MERTK kinase and functional activities highlights that MERTK kinase inhibition may not be sufficient to block all MERTK-dependent oncogenic functions and, at least in some cases, down-regulation of total MERTK by antibody-mediated approaches or novel developing technologies, such as biochemical degraders, may be a more effective therapeutic strategy.

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control MERTK genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

Service	Details	Alternative cell lines or animal species
MERTK Gene Editing Cell Line Generation	gRNA design and synthesis Transfect the cell pnes you're interested Select the high expression cells and sort monoclonal cell Vapdate the knockout/knockin/point mutation of CD40 by PCR and sequencing Provide cryogenic preserved vials of stable cells and final reports	HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
MERTK Gene Editing Animal Model	MERTK gene conventional knockout animals	Mouse, rat, rabbit, zebrafish, C. elegans, etc.
Generation	MERTK gene conventional knockout animals MERTK gene conditional knockout animals MERTK point mutation animals MERTK knockin animals

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