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Pharmacol Ther. 2015 Feb;146:132-49. doi: 10.1016/j.pharmthera.2014.10.001. Epub 2014 Oct 12.

FAK signaling in human cancer as a target for therapeutics.

Author information

1
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
2
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
3
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia; The Chris O'Brien Lifehouse, Camperdown, NSW 2050, Australia; Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia; University of Sydney, Camperdown, NSW 2050, Australia.
4
St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia; Department of Biochemistry and Molecular Biology, Faculty of Biomedical and Psychological Sciences, Monash University, Clayton, VIC 3800, Australia. Electronic address: roger.daly@monash.edu.

Abstract

Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.

KEYWORDS:

Cancer stem cells; Metastasis; Scaffold protein; Tumorigenesis; Tyrosine kinase; Tyrosine kinase inhibitor

[Indexed for MEDLINE]

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