MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme

Knubel, Kristina H.; Pernu, Ben M.; Sufit, Alexandra; Nelson, Sarah J.; Pierce, Angela; Keating, Amy K.

doi:10.18632/oncotarget.1793

Cited by 51 publications

(37 citation statements)

References 43 publications

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“…Interestingly, migration was only reduced with a complete MERTK knockdown, which was accompanied by decreased RhoA expression. The association of MERTK with cell motility has previously been shown in melanoma, glioblastoma and non-tumorigenic breast epithelial cell lines [22, 35, 37]. In contrast to our results MERTK knockdown in glioblastoma cells decreased migration but increased FAK and RhoA expression [38].…”

Section: Discussioncontrasting

confidence: 69%

MERTK as a novel therapeutic target in head and neck cancer

et al. 2016

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Although head and neck cancer (HNSCC) is the sixth most common tumor entity worldwide therapy options remain limited leading to 5-year survival rates of only 50 %. MERTK is a promising therapeutic target in several tumor entities, however, its role in HNSCC has not been described yet. The aim of our study was to investigate the biological significance of MERTK and to evaluate its potential as a novel therapeutic target in this dismal tumor entity. In two large HNSCC cohorts (n=537 and n=520) we found that MERTK is overexpressed in one third of patients. In-vitro, MERTK overexpression led to increased proliferation, migration and invasion whereas MERTK inhibition with the small molecule inhibitor UNC1062 or MERTK knockdown reduced cell motility via the small GTPase RhoA.Taken together, we are the first to show that MERTK is frequently overexpressed in HNSCC and plays an important role in tumor cell motility. It might therefore be a potential target for selected patients suffering from this dismal tumor entity.

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Section: Discussioncontrasting

confidence: 69%

MERTK as a novel therapeutic target in head and neck cancer

et al. 2016

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“…Currently, there are no selective Food and Drug Administration (FDA)-approved inhibitors of MERTK or NTRK2. The multikinase inhibitor foretinib inhibits MERTK in addition to c-MET and VEGFR (59). Because c-MET inhibition is effective in some patients with metastatic prostate cancer, targeting both MERTK and c-Met with foretinib may be a promising therapeutic approach (60).…”

Section: Discussionmentioning

confidence: 99%

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier

Drake

Clark

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.kinases | metastasis | prostate cancer | bone metastasis M etastatic prostate cancer is responsible for the deaths of ∼30,000 men in the United States each year (1, 2). Ninety percent of patients develop bone metastases, and other major sites of metastases include lymph nodes, liver, adrenal glands, and lung (3). First-line treatments for metastatic disease are androgen deprivation therapies that block androgen synthesis or signaling through the androgen receptor (AR) (2). Inevitably, metastatic prostate cancer becomes resistant to androgen blockade. Second-line treatments such as chemotherapy (docetaxel, cabazitaxel) and radiation only extend survival 2-4 mo (4, 5).Identifying new therapeutic targets for metastatic prostate cancer has proven difficult. Exome and whole-genome sequencing of human metastatic prostate cancer tissues have found frequent mutations and/or chromosomal aberrations in numerous genes, including AR, TP53, PTEN, BRCA2, and MYC (6-11). The precise functional contribution of these genes to prostate cancer metastasis remains unknown. Genomic and phosphoproteomic analyses have also revealed that metastatic prostate cancer is molecularly heterogeneous, which has complicated the search for common therapeutic targets (12). Few murine models of prostate cancer develop metastases. Mice having prostate-specific homozygous deletions in SMAD4 and PTEN or expression of mutant KRAS develop metastases in visceral organs but rarely in bone (13-15).Targeting genetically altered constitutively active protein kinases such as BCR-ABL in chronic myelogenous leukemia and BRAF V600E in melanoma has led to dramat...

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“…Mechanistically, TAM receptor signaling supports several key cellular events in the tumor, from cell growth and survival, to metastasis, epithelial-mesenchymal transition (EMT), and resistance to chemotherapy [20,22,23,24,122,123,124,125]. Importantly, experimental evidence demonstrates that TAM antagonism can efficiently revert these processes [22,126,127,128,129,130], underscoring the potential benefits of TAM inhibition for cancer therapy (Figure 3). Together, these consistent results have encouraged the development of novel and specific ways of inhibiting TAM signaling in tumor cells for clinical use [24,131,132].…”

Section: Taming Anti-tumor Immunitymentioning

confidence: 99%

“…Most in vivo studies exploring the cell autonomous pro-oncogenic role of TAM receptors employ human cancer cells in immunodeficient mice [49,123,126,127,136], therefore preventing the elucidation of the immune system’s contribution. The first indication that TAM signaling affects anti-tumor immunity came from genetic studies of Gas6-deficient mice, where absence of Gas6 in hematopoietic cells markedly impaired tumor proliferation and metastasis in diverse ectopic and orthotopic tumor models, including pancreatic, lymphoma, colon, breast, and melanoma tumors [27].…”

Section: Taming Anti-tumor Immunitymentioning

confidence: 99%

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

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The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

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MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme

Cited by 51 publications

References 43 publications

MERTK as a novel therapeutic target in head and neck cancer

MERTK as a novel therapeutic target in head and neck cancer

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

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