Focal adhesion kinase

Stone, Rebecca L.; Baggerly, Keith A.; Armaiz-Pena, Guillermo N.; Kang, Yu; Sanguino, Ángela; Thanapprapasr, Duangmani; Dalton, Heather J.; Bottsford-Miller, Justin; Zand, Behrouz; Akbani, Rehan; Li, Diao; Nick, Alpa M.; DeGeest, Koen; López-Berestein, Gabriel; Coleman, Robert L.; Lutgendorf, Susan K.; Sood, Anil K.

doi:10.4161/cbt.28882

Cited by 44 publications

(15 citation statements)

References 49 publications

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“…Moreover, nuclear-localized form of FAK may process unique functions, and its expression was associated with patient’s survival in some tumors [ 12 , 13 ]. The major site of autophosphorylation in the FAK catalytic domain at tyrosine 397 is very important for FAK function leading to many downstream signaling cascades of cell proliferation, migration, and angiogenesis [ 14 , 15 ]. Recently, in order to inhibit FAK activity, a number of small molecule ATP-competitive kinase inhibitors have been developed, as well as more specific inhibitors, that target particular kinase domain sites of FAK by blocking access to the FAK at tyrosine 397.…”

Section: Introductionmentioning

confidence: 99%

pFAK-Y397 overexpression as both a prognostic and a predictive biomarker for patients with metastatic osteosarcoma

et al. 2017

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Focal adhesion kinase (FAK) is important for tumor cell survival and metastasis in various cancers. However, its expression and prognostic value in patients with metastatic osteosarcoma remain unknown. We investigated the expression of FAK and its phosphorylated form (pFAK-Y397) in osteosarcoma tissues from 53 patients by immunohistochemistry and evaluated their correlations with clinicopathologic characteristics and outcomes. The prognostic values were assessed using Kaplan-Meier survival and Cox regression analyses. Total FAK and pFAK-Y397 were overexpressed in 48 (90.6%) and 33 (62.3%) cases, respectively. pFAK-Y397 overexpression was correlated with poor histologic response after neoadjuvant chemotherapy in patients with osteosarcoma regardless of the presence of metastasis or not. Kaplan-Meier curve showed that patients with metastatic osteosarcoma with pFAK-Y397 overexpression had significantly worse overall survival (OS) than those with non-overexpression (P = 0.044). Multivariate Cox regression analysis confirmed pFAK-Y397 overexpression as an independent prognostic predictor for OS and post metastases OS (PMOS) (P = 0.017, P = 0.006, respectively). Age at diagnosis was also an independent indicator for PMOS (P = 0.003). However, total FAK expression was not correlated with any clinicopathologic characteristics or OS in patients with metastatic osteosarcoma. In conclusion, our findings identified FAK as a common aberrant protein overexpression in various subtypes of osteosarcoma. pFAK-Y397 overexpression can be used as a prognostic biomarker predicting poor OS for patients with metastatic osteosarcoma, and the expression of pFAK-Y397 differentiated good and poor responders to neoadjuvant chemotherapy.

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Section: Introductionmentioning

confidence: 99%

pFAK-Y397 overexpression as both a prognostic and a predictive biomarker for patients with metastatic osteosarcoma

et al. 2017

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“…Based on the studies of the integrin–FAK signaling axis, 19 , 33 we also evaluated the effect of the VS-6063 and JQ1 combination on the chemoresistance of ovarian cancer. Our data showed that in multiple ovarian cancer cell lines, treatment with a low concentration of VS-6063 alone actually led to more resistance to paclitaxel in ovarian cancer cells ( Figure 8a ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy

Lefringhouse

Liu

et al. 2017

Oncogenesis

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Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin–FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.

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“…This inhibition depends on CS in CSPG because chondroitinase pretreatment abolished the inhibition. FAK signaling is also important for angiogenesis [31] . Thus, inhibition of angiogenesis by CSPG might also occur through inhibition of FAK phosphorylation by the CS chain.…”

Section: Discussionmentioning

confidence: 99%

Chondroitin sulfate proteoglycans from salmon nasal cartilage inhibit angiogenesis

Kobayashi

Kakizaki

Nozaka

et al. 2017

Biochemistry and Biophysics Reports

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Because cartilage lacks nerves, blood vessels, and lymphatic vessels, it is thought to contain factors that inhibit the growth and development of those tissues. Chondroitin sulfate proteoglycans (CSPGs) are a major extracellular component in cartilage. CSPGs contribute to joint flexibility and regulate extracellular signaling via their attached glycosaminoglycan, chondroitin sulfate (CS). CS and CSPG inhibit axonal regeneration; however, their role in blood vessel formation is largely unknown. To clarify the function of CSPG in blood vessel formation, we tested salmon nasal cartilage proteoglycan (PG), a member of the aggrecan family of CSPG, for endothelial capillary-like tube formation. Treatment with salmon PG inhibited endothelial cell adhesion and in vitro tube formation. The anti-angiogenic activity was derived from CS in the salmon PG but not the core protein. Salmon PG also reduced matrix metalloproteinase expression and inhibited angiogenesis in the chick chorioallantoic membrane. All of these data support an anti-angiogenic role for CSPG in cartilage.

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Focal adhesion kinase

Cited by 44 publications

References 49 publications

pFAK-Y397 overexpression as both a prognostic and a predictive biomarker for patients with metastatic osteosarcoma

pFAK-Y397 overexpression as both a prognostic and a predictive biomarker for patients with metastatic osteosarcoma

Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy

Chondroitin sulfate proteoglycans from salmon nasal cartilage inhibit angiogenesis

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