A Novel Small Molecule Inhibitor of FAK and IGF-1R Protein Interactions Decreases Growth of Human Esophageal Carcinoma

Uçar, Deniz A.; Cox, Audrey; He, Di-Hua; Ostrov, David A.; Kurenova, Elena; Hochwald, Steven N.

doi:10.2174/187152011796817718

Cited by 12 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, normal cell lines such MCF10A and melanocytes are much less sensitive to INT2-31, demonstrating the increased sensitivity of cancer cells to this small molecule compound. Indeed, our previous results support this as well [22]. …”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

Uçar¹,

Magis²,

He³

et al. 2013

ACAMC

Self Cite

View full text Add to dashboard Cite

Pancreatic cancer is one of the most lethal diseases with no effective treatment. Previously, we have shown that FAK is overexpressed in pancreatic cancer and plays a key role in cancer cell survival and proliferation. FAK has been shown to interact with growth factor receptors including cMET and IGF-1R. As a novel therapeutic approach, we targeted the protein interaction of FAK with growth factor receptors to block tumor growth, alter signaling pathways and sensitize cells to chemotherapy. We have selected a small molecule compound (INT2-31) that decreases phosphorylation of AKT via disrupting interaction of FAK with cMET and IGF-1R. Our results demonstrate that interaction of a small molecule compound with FAK decreases phosphorylation of FAK Y397 while increasing FAK Y407 phosphorylation, without inhibiting the kinase activity of FAK and dramatically reduces downstream signaling to AKT. Our lead compound, INT2-31, demonstrates significant inhibition of tumor cell growth in two orthotopic models of pancreatic cancer. In addition, INT2-31increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer growth.

show abstract

Section: Discussionsupporting

confidence: 87%

“…MiaPaca-2 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% FBS, 2.5% horse serum and 1 µg/ml penicillin–streptomycin. Other cell lines were obtained and cultured as we described previously [22]. …”

Section: Methodsmentioning

confidence: 99%

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

Uçar¹,

Magis²,

He³

et al. 2013

ACAMC

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, allosteric FAK inhibitor Y15, targeting major autophosphorylation site of FAK Y397, which affects not only FAK kinase activity but, more importantly, FAK interactions with Src and PI3K, showed promising results in treatment of breast, pancreatic, colon and glioblastoma cancers [49]. PPI inhibitor NT2-31 targeted to the FAK-IGF-1R site of interaction dramatically reduced growth of melanoma, pancreatic and gastric cancers and show synergy with chemotherapy [22, 50]. …”

Section: Discussionmentioning

confidence: 99%

“…Targeting cancer survival pathways with the drugs targeted to the scaffold is emerging as a promising novel approach [21]. Data on targeting specific protein-protein interactions of FAK demonstrate encouraging results in multiple cancer models, including PDA [22, 23]. One of the important components of the FAK scaffold is vascular endothelial growth factor receptor 3 (VEGFR-3 or Flt4).…”

Section: Introductionmentioning

confidence: 99%

The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth

Kurenova

Liao²,

He³

et al. 2013

Oncotarget

Self Cite

View full text Add to dashboard Cite

Even with successful surgical resection and perioperative chemotherapy and radiation, pancreatic ductal adenocarcinoma (PDA) has a high incidence of recurrence. Tumor cell survival depends on activation of signaling pathways that suppress the apoptotic stimuli of invasion and metastasis. Focal adhesion kinase (FAK) is a critical signaling molecule that has been implicated in tumor cell survival, invasion and metastasis. We have previously shown that FAK and vascular endothelial growth factor receptor 3 (VEGFR-3) are overexpressed in cancer cells and physically interact to confer a significant survival advantage. We subsequently identified a novel small molecule inhibitor C4 that targeted the VEGFR-3-FAK site of interaction. In this study, we have shown that C4 disrupted the FAK-VEGFR-3 complexes in PDA cells. C4 treatment caused dose-dependent dephosphorylation and inactivation of the VEGFR-3 and FAK, reduction in cell viability and proliferation, cell cycle arrest and apoptosis in PDA cells. C4 increased the sensitivity of tumor cells to gemcitabine chemotherapy in vitro that lead to apoptosis at nanomolar concentrations of both drugs. C4 reduced tumor growth in vivoin subcutaneous and orthotopic murine models of PDA. The drug alone at low dose, decreased tumor growth; however, concomitant administration with low dose of gemcitabine had significant synergistic effect and led to 70% tumor reduction. Combination of C4 with gemcitabine had a prolonged cytostatic effect on tumor growth after treatment withdrawal. Finally, we report an anecdotal case of stage IV pancreatic cancer treated with gemcitabine in combination with C4 that showed a significant clinical response in primary tumor and complete clinical response in liver metastasis over an eight month period. Taken together, these results demonstrate that targeting the scaffolding function of FAK with a small-molecule FAK-VEGFR-3 inhibitor can be an effective therapeutic strategy against PDA.

show abstract

“…After stimulation with IGF-I, the phosphorylated IGR-IR (p-IGF-IR) was detected at the cell border only in control cells, but not after treatment with cathepsin X-specific siRNAs ( Figure 3B). Focal adhesion kinase (FAK) is known to interact with the activated IGF-IR and mediates IGF-I signals (Liu et al , 2008 ;Andersson et al , 2009 ;Ucar et al , 2011 ). Co-immunostaining with p-FAK showed a similar staining pattern to the p-IGF-IR at the cell periphery in control cells but not in cathepsin X-deficient cells.…”

mentioning

confidence: 97%

IGF-I receptor phosphorylation is impaired in cathepsin X-deficient prostate cancer cells

Kraus¹,

Fruth

Bunsen

et al. 2012

Biological Chemistry

View full text Add to dashboard Cite

Abstract:The cysteine-type peptidase cathepsin X is highly upregulated in several cancers and presumably promotes tumor invasion through bypassing cellular senescence. Here, we present first evidence that the underlying mechanism may involve the regulation of the insulin-like growth factor (IGF) system, a well-known activator of proliferating tumor cells. Cathepsin X deficiency leads to a reduced phosphorylation of the IGF-I receptor in response to IGF-I stimulation. In addition, downstream signaling through focal adhesion kinase was also affected. Taken together, our results indicate that cathepsin X is able to assist in IGF signaling, which may be an important progress toward understanding cathepsin X-dependent tumorigenesis.

show abstract

A Novel Small Molecule Inhibitor of FAK and IGF-1R Protein Interactions Decreases Growth of Human Esophageal Carcinoma

Cited by 12 publications

References 0 publications

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth

IGF-I receptor phosphorylation is impaired in cathepsin X-deficient prostate cancer cells

Contact Info

Product

Resources

About