A Small-molecule Inhibitor, 5'-O-Tritylthymidine, Targets FAK and Mdm-2 Interaction, and Blocks Breast and Colon Tumorigenesis in vivo

Golubovskaya, Vita M.; Palma, Nadia L.; Zheng, Min; Ho, Baotran; Magis, Andrew T.; Ostrov, David A.; Cance, William G.

doi:10.2174/1871520611313040002

Cited by 28 publications

(28 citation statements)

References 23 publications

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“…Since FAK blocks functions of tumor suppressor proteins, another approach is to disrupt FAK interaction with these proteins and reactivate their tumor-suppressor functions. The first approach to target the scaffolding function of FAK was performed by disrupting FAK and VEGFR-3(134) with C4, then disrupting FAK and IFGR1 interaction, FAK and c-Met with INT2-31 inhibitor (135–136); and then FAK and Mdm-2 interaction (137) with M13 inhibitor and recently FAK and p53 interaction with R2 inhibitor (138). These inhibitors effectively targeted the scaffolding function of FAK and inhibited cancer cell viability and tumor growth through disrupting angiogenesis, inhibition of AKT signaling or activating p53 signaling with activating down-stream targets of p53: p21, Bax and Mdm-2 (138).…”

Section: Targeting Fak With Inhibitorsmentioning

confidence: 99%

Targeting FAK in human cancer: from finding to first clinical trials

2014

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It is twenty years since Focal Adhesion Kinase (FAK) was found to be overexpressed in many types of human cancer. FAK plays an important role in adhesion, spreading, motility, invasion, metastasis, survival, angiogenesis, and recently has been found to play an important role as well in epithelial to mesenchymal transition (EMT), cancer stem cells and tumor microenvironment. FAK has kinase-dependent and kinase independent scaffolding, cytoplasmic and nuclear functions. Several years ago FAK was proposed as a potential therapeutic target; the first clinical trials were just reported, and they supported further studies of FAK as a promising therapeutic target. This review discusses the main functions of FAK in cancer, and specifically focuses on recent novel findings on the role of FAK in cancer stem cells, microenvironment, epithelial-to-mesenchymal transition, invasion, metastasis, and also highlight new approaches of targeting FAK and critically discuss challenges that lie ahead for its targeted therapeutics. The review provides a summary of translational approaches of FAK-targeted and combination therapies and outline perspectives and future directions of FAK research.

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Section: Targeting Fak With Inhibitorsmentioning

confidence: 99%

Targeting FAK in human cancer: from finding to first clinical trials

2014

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“…Since we detected p53-dependent up-regulation of Mdm-2 expression (Table 1) in HCT116p53 +/+ cells, and Mdm-2 was shown to bind FAK to down-regulate p53, providing survival to cancer cells [11], we used compound M13 that disrupted interaction of FAK and Mdm-2, called M13 that up-regulated p53 activity and caused apoptosis in HCT116 p53 +/+ cells [14] in combination with R2 in clonogenicity assay to test if combination of R2 and M13 will decrease cancer cell clonogenicity more effectively than each agent alone. Figure 3A shows that combination of R2 and M13 is more effective in decreasing clonogenicity of HCT116 p53 +/+ cells than each agent alone.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex

Golubovskaya

Conroy

et al. 2014

Cancers

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Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53−/− cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53+/+ cells but not in p53−/− cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach.

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“…96 They have also shown an interaction between MDM2 and FAK, and that interruption of the MDM2-FAK interaction with a small molecule resulted in decreased breast and colon tumor cell growth in vitro and in vivo . 97 Recent data in our laboratory indicate that p53 and FAK interact in neuroblastoma cell lines (Fig. 1) and that inhibition of the p53 and FAK interaction with interfering peptides results in decreased neuroblastoma tumor cell survival (Fig.…”

Section: Neuroblastoma and Transcription Factorsmentioning

confidence: 89%

Cell Survival Signaling in Neuroblastoma

Megison¹,

Gillory²,

Beierle³

2013

ACAMC

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Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma.

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A Small-molecule Inhibitor, 5'-O-Tritylthymidine, Targets FAK and Mdm-2 Interaction, and Blocks Breast and Colon Tumorigenesis in vivo

Cited by 28 publications

References 23 publications

Targeting FAK in human cancer: from finding to first clinical trials

Targeting FAK in human cancer: from finding to first clinical trials

Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex

Cell Survival Signaling in Neuroblastoma

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