Inhibition of FAK and VEGFR‐3 binding decreases tumorigenicity in neuroblastoma

Stewart, Jerry E.; Ma, Xiaojie; Megison, Michael L.; Nabers, Hugh C.; Cance, William G.; Kurenova, Elena; Beierle, Elizabeth A.

doi:10.1002/mc.22070

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…Recently, it was shown that interference with several FAK protein-protein interactions has a dramatic effect on cancer cell survival and progression. [49][50][51][52] During the course of our study, Megison et al 29 demonstrated that in vitro and in vivo abrogation of FAK impacted cancer cell survival and growth in pediatric kidney tumors. Here, we show that FAK is critically associated both in vitro and in vivo with human renal carcinogenesis in adults.…”

Section: Cancer Cell Biologymentioning

confidence: 67%

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Targeting FAK scaffold functions inhibits human renal cell carcinoma growth

Beraud

Dormoy

Danilin

et al. 2015

Intl Journal of Cancer

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Human conventional renal cell carcinoma (CCC) remains resistant to current therapies. Focal Adhesion Kinase (FAK) is upregulated in many epithelial tumors and clearly implicated in nearly all facets of cancer. However, only few reports have assessed whether FAK may be associated with renal tumorigenesis. In this study, we investigated the potential role of FAK in the growth of human CCC using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as well as normal/tumoral renal tissue pairs. FAK was found constitutively expressed in human CCC both in culture cells and freshly harvested tumors obtained from patients. We showed that CCC cell growth was dramatically reduced in FAK-depleted cells or after FAK inhibition with various inhibitors and this effect was obtained through inhibition of cell proliferation and induction of cell apoptosis. Additionally, our results indicated that FAK knockdown decreased CCC cell migration and invasion. More importantly, depletion or pharmacological inhibition of FAK substantially inhibited tumor growth in vivo. Interestingly, investigations of the molecular mechanism revealed loss of FAK phosphorylation during renal tumorigenesis impacting multiple signaling pathways. Taken together, our findings reveal a previously uncharacterized role of FAK in CCC whereby FAK exerts oncogenic properties through a non canonical signaling pathway involving its scaffolding kinase-independent properties. Therefore, targeting the FAK scaffold may represent a promising approach for developing innovative and highly specific therapies in human CCC.Renal cell carcinoma (RCC) is the eighth most common cancer and the most lethal urological tumor, accounting for 110,000 deaths worldwide. 1 Its incidence continues to increase by 2% yearly. Five types of RCC have been delineated. Overall, 75% of RCC is of the clear cell type (CCC), originating from the renal proximal tubule. At early stages, partial or complete resection is the most effective treatment for localized tumors. However, 30% of patients are diagnosed with a metastatic disease and one-third of initially metastasis-free patients develop metastasis after the initial surgery. 2 Standard approaches including radio-and chemotherapy have consistently failed at the metastatic stage, placing RCC among the most resistant cancer. Recent studies yielded a better knowledge of the molecular mechanisms of renal tumorigenesis and led to the development of antiangiogenic strategies now used as first-line therapy such as anti-VEGF antiboby (Bevacizumab), multiple tyrosine kinase inhibitors (Sunitinib, Sorafenib) and mTOR inhibitors (Temsirolimus, Everolimus). These drugs have been approved for the treatment of advanced CCC improving the progression free survival but without effect on overall survival. 3,4 Moreover, the antitumoral activity of these compounds is limited in time due to the development of tumor resistance. So far, the best known oncogenic signal in human CCC is constituted by the von Hippel-Lindau (VHL) tumo...

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Section: Cancer Cell Biologymentioning

confidence: 67%

“…Although this pharmacological strategy is in its infancy, FAK scaffold interaction can be disrupted by peptides or small molecule inhibitors. Recently, it was shown that interference with several FAK protein‐protein interactions has a dramatic effect on cancer cell survival and progression …”

Section: Discussionmentioning

confidence: 99%

Targeting FAK scaffold functions inhibits human renal cell carcinoma growth

Beraud

Dormoy

Danilin

et al. 2015

Intl Journal of Cancer

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“…Despite the common somatic 17q gain, we found significant divergence of somatic CN and mutational variants across samples, similar to what has been described in multifocal lung cancer, prostate cancer, and glioblastoma, suggesting true multifocal primary sites of disease with independent development of tumors rather than oligometastatic spread. All somatic mutations identified were present in no more than two samples, although several have been described to have oncogenic potential and relevance in neuroblastoma, including FBN1 , FLT4/VEGFR3 , and N4BP1 (Table S1). Additional functional study of the listed genes may provide novel insight into neuroblastoma pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Multifocal primary neuroblastoma tumor heterogeneity in siblings with co‐occurring PHOX2B and NF1 genetic aberrations

Rybinski

Wolinsky

Brohl

et al. 2019

Genes Chromosomes & Cancer

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Neuroblastoma, the most common extracranial solid tumor of childhood, can present in multiple primary sites, but the extent of genetic heterogeneity among tumor foci, as well as the presence or absence of common oncogenic drivers, remains unknown. Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development. We performed comprehensive molecular characterization of neuroblastoma tumors from two siblings affected by familial multifocal neuroblastoma, including whole exome sequencing and single‐nucleotide polymorphism (SNP) arrays of tumor and matched blood samples. Data were processed and analyzed using established bioinformatics algorithms to evaluate for germline and somatic mutations and copy number variations (CNVs). We confirmed the presence of a PHOX2B deletion and NF1 mutation across all tumor samples and the germline genome. Matched tumor‐blood whole exome sequencing also identified 365 genes that contained nonsilent coding mutations across all tumor samples, with no recurrent mutations across all tumors. SNP arrays also showed significant heterogeneity with respect to CNVs. The only common CNV across all tumors was 17q gain, with differing chromosomal coordinates across samples but a common region of overlap distal to 17q21.31, suggesting this adverse prognostic biomarker may offer insight about additional drivers for multifocal neuroblastoma in patients with germline PHOX2B or NF1 aberrations. Molecular characterization of all tumors from patients with multifocal primary neuroblastoma has potential to yield novel insights on neuroblastoma pathogenesis.

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“…FAK has also been shown to associate with IGF-1R in both pancreatic cancer cell lines MiaPaca-2 and Panc-1, providing a mechanism for increased cellular survival [38]. Previously, our laboratory found that FAK had a direct accociation with VEGFR-3 in human neuroblastoma cell lines, and that interruption of that association with peptides or small molecules resulted in decreased cellular survival in vitro and decreased tumor growth in vivo [39]. In addition to binding to the oncogene p53 [17, 18], FAK has also been shown to bind to the tumor suppressor, neurofibromin [40].…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival

Gillory

Stewart

Megison

et al. 2015

Journal of Surgical Research

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Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is important in many facets of neuroblastoma tumor development and progression. The p53 oncogene, although wild type in most neuroblastomas, lacks significant function as a tumor suppressor in these tumors. Recent reports have found that FAK and p53 interact in some tumor types. We have hypothesized FAK and p53 coordinately control each other’s expression and also interact in neuroblastoma. In the current study, we showed that not only do FAK and p53 interact but each one controls the expression of the other. In addition, we also examined the effects of FAK inhibition combined with p53 activation in neuroblastoma and showed that these two, in combination, had a synergistic effect upon neuroblastoma cell survival. The findings from this current study help to further our understanding of the regulation of neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for neuroblastoma and other pediatric solid tumors.

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Inhibition of FAK and VEGFR‐3 binding decreases tumorigenicity in neuroblastoma

Cited by 19 publications

References 46 publications

Targeting FAK scaffold functions inhibits human renal cell carcinoma growth

Targeting FAK scaffold functions inhibits human renal cell carcinoma growth

Multifocal primary neuroblastoma tumor heterogeneity in siblings with co‐occurring PHOX2B and NF1 genetic aberrations

Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival

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