Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer

Ferguson, Benjamin D.; Tan, Yulong; Kanteti, Rajani; Liu, Ren; Gayed, Matthew; Vokes, Everett E.; Ferguson, Mark K.; Iafrate, A. John; Gill, Parkash S.; Salgia, Ravi

doi:10.1038/srep10641

Cited by 23 publications

(25 citation statements)

References 59 publications

(53 reference statements)

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“…Enhanced apoptosis is one of the key anti-tumor responses mediated by EphB4 targeting and radiation325262728. In caspase-3/7 assay, we observed a significant increase in apoptosis (~28%) in Fadu cells transfected with EphB4-siRNA and 4 Gy dose of radiation compared to radiation alone at 96 h (Fig.…”

Section: Resultsmentioning

confidence: 72%

“…Ferguson et al . have shown that in lung carcinoma cells, EphB4 knockdown affects apoptosis by altering the expression of the JAK-STAT family of proteins25. Another study by Pradeep et al .…”

Section: Discussionmentioning

confidence: 97%

“…Enhanced apoptosis is one of the main mechanisms underlying the anti-tumorigenic effects of sEphB4-HSA treatment325263940. Reports suggest that DNA damage is a causative factor of apoptosis following radiation24.…”

Section: Discussionmentioning

confidence: 99%

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Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas

Sharma

Oweida

Griego

et al. 2016

Sci Rep

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Members of the Eph family of receptor tyrosine kinases have been implicated in a wide array of human cancers. The EphB4 receptor is ubiquitously expressed in head and neck squamous cell carcinoma (HNSCC) and has been shown to impart tumorigenic and invasive characteristics to these cancers. In this study, we investigated whether EphB4 receptor targeting can enhance the radiosensitization of HNSCC. Our data show that EphB4 is expressed at high to moderate levels in HNSCC cell lines and patient-derived xenograft (PDX) tumors. We observed decreased survival fractions in HNSCC cells following EphB4 knockdown in clonogenic assays. An enhanced G2 cell cycle arrest with activation of DNA damage response pathway and increased apoptosis was evident in HNSCC cells following combined EphB4 downregulation and radiation compared to EphB4 knockdown and radiation alone. Data using HNSCC PDX models showed significant reduction in tumor volume and enhanced delay in tumor regrowth following sEphB4-HSA administration with radiation compared to single agent treatment. sEphB4-HSA is a protein known to block the interaction between the EphB4 receptor and its ephrin-B2 ligand. Overall, our findings emphasize the therapeutic relevance of EphB4 targeting as a radiosensitizer that can be exploited for the treatment of human head and neck carcinomas.

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Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 97%

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Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas

Sharma

Oweida

Griego

et al. 2016

Sci Rep

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“…EPHB4 plays a crucial role in cardiovascular development and regulates vascularization in cancer‐promoting angiogenesis, tumour growth and metastasis 41 . Several EPHB4 mutations have previously been identified in solid and haematological tumour specimens 42‐44 . Many other variants in other types of tumours and cell lines have been identified and catalogued in “The Cancer Genome Atlas project” 24 .…”

Section: Discussionmentioning

confidence: 99%

Kinome multigenic panel identified novel druggable EPHB4‐V871I somatic variant in high‐risk neuroblastoma

Andolfo

Lasorsa

Manna

et al. 2020

J Cellular Molecular Medi

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Neuroblastoma (NB) is the most common extracranial neoplasm in children. The overall outcome for high‐risk NB patients is still unacceptable, therefore, it is critical to deeply understand molecular mechanisms associated with NB, which in turn can be utilized for developing drugs towards the treatment of NB. Protein kinases (TKs) play an essential role in the regulation of cell survival and proliferation. Different kinases, such as anaplastic lymphoma kinase (ALK), Aurora kinase, RET receptor tyrosine kinase, are potential therapeutic targets in various cancers, including NB. We analysed a cohort of 45 high‐risk NB patients and 9 NB cell lines by a targeted—(t)NGS custom gene panel (genes codifying for the kinase domains of 90 TKs). We identified somatic variants in four TK genes (ALK, EPHB4, LMTK3 and EPHB6) in NB patients and we functionally characterized an interesting somatic variant, V871I, in EPHB4 gene. EPHB4 plays a crucial role in cardiovascular development and regulates vascularization in cancer‐promoting angiogenesis, tumour growth and metastasis. Several EPHB4 mutations have previously been identified in solid and haematological tumour specimens but EPHB4 mutations were not described until now in NB. Interestingly, a re‐analysis of public CGH‐array showed that the EPHB4 gain is associated with advanced diseases in NB. We further demonstrated that higher EPHB4 expression is correlated to stage 4 of NB and with poor overall survival. Additionally, we also revealed that the EPHB4‐V871I accounts for increased proliferation, migration and invasion properties in two NB cell lines by acting on VEGF, c‐RAF and CDK4 target genes and by increasing the phosphorylation of ERK1‐2 pathway. The use of two EPHB4 inhibitors, JI‐101 and NVP‐BHG712, was able to rescue the phenotype driven by the variant. Our study suggested that EPHB4 is a promising therapeutic target in high‐risk NB.

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“…15,16 EPHB4 mutations have been reported in some epithelial cancers, such as lung cancer, whereas EPHB4 gene amplification occurs in nearly one-third of head and neck cancers. 17,18 Furthermore, we have shown that EGFR activation, loss of PTEN, or Kras G12D activating mutations induce EPHB4 (Xi et al, 8 Masood et al, 17 Huang and Li, 19 and P.S.G., unpublished data). Despite this wealth of data describing EPHB4/ephrinB2 in cancer, very little has been published about this pathway in leukemia.…”

Section: Introductionmentioning

confidence: 99%

EPHB4 is a therapeutic target in AML and promotes leukemia cell survival via AKT

et al. 2017

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Key Points• EPHB4 promotes leukemia survival via AKT activation.• EPHB4 can be therapeutically targeted in AML with monoclonal antibodies.EPHB4, an ephrin type B receptor, is implicated in the growth of several epithelial tumors and is a promising target in cancer therapy; however, little is known about its role in hematologic malignancies. In this article, we show that EPHB4 is highly expressed in ;30% of acute myeloid leukemia (AML) samples. In an unbiased RNA interference screen of primary leukemia samples, we found that EPHB4 drives survival in a subset of AML cases.Knockdown of EPHB4 inhibits phosphatidylinositol 3-kinase/AKT signaling, and this is accompanied by a reduction in cell viability, which can be rescued by a constitutively active form of AKT. Finally, targeting EPHB4 with a highly specific monoclonal antibody (MAb131) is effective against AML in vitro and in vivo. EPHB4 is therefore a potential target in AML with high EPHB4 expression.

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Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer

Cited by 23 publications

References 59 publications

Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas

Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas

Kinome multigenic panel identified novel druggable EPHB4‐V871I somatic variant in high‐risk neuroblastoma

EPHB4 is a therapeutic target in AML and promotes leukemia cell survival via AKT

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