Focal Adhesion Kinase: Targeting Adhesions Signals in Normal and Cancer Cells
Authors: J. Parsons, Jill Slack-Davis, Robert Tilghman, Marcin Iwanicki, Ethan Ung, Christopher Autry, Michael Luzzio, Howard Fingert, Gregory Roberts
Journal: Clinical Cancer Research (2007)

PL04-03  Focal Adhesion Kinase (FAK) is a member of a family of non-receptor protein tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation and cell survival. FAK expression is increased in many cancers, indicating that FAK could be a target for therapeutic intervention. In normal cells FAK is activated upon integrin engagement and serves to mediate signals from the extracellular matrix. A key role for FAK is the regulation of adhesion turnover required for cell migration. Deletion of FAK or inhibition of FAK expression/activity leads to defects in cell migration. A variety of approaches have been used to validate FAK as a target for therapeutic intervention in human and mouse models of cancer, including expression of dominant negative forms of FAK, siRNA knockdown experiments and tissue-specific deletion of FAK in mice bearing floxed alleles of FAK. Each of these experimental approaches has supported a role for FAK in aspects of tumor initiation, development and progression. Recently, small molecule inhibitors of FAK have been identified and characterized. PF-573,228, is an ATP competitive inhibitor of FAK and inhibits recombinant FAK in vitro with an IC50 of 3-4 nM, blocks in vivo FAK auto-phosphorylation in normal fibroblasts and human tumor cell lines with an IC50 of approximately 300-500nM, and inhibits cell migration by blocking adhesion turnover. However, PF-573,228 has no effect on cell growth and does not induce apoptosis in fibroblasts. A second compound, PF-562,271 (currently in phase I clinical trials) is a potent inhibitor of both FAK and the related kinase, Pyk2 with IC50 of 1.5 and 14 nM, respectively. PF-562,271 exhibits greater than 100-fold selectivity for FAK and Pyk2 when assayed against a long list of non-target kinases. In preclinical animal models, PF-562,271 inhibited FAK phosphorylation in vivo in a dose dependent fashion in several human subcutaneous xenograft models, including: PC-3M (prostate), BT474 (breast), BxPc3 (pancreatic), LoVo (colon), U87MG (glioblastoma), and H460 (lung). Treatment of cultured fibroblasts, epithelial cells, or prostate, ovarian, and pancreatic cancer cells with PF-562,271 resulted in a dose dependent decrease in FAK auto-phosphorylation with an IC50 of 10-30 nM and maximal inhibition with 100-300 nM. Treatment with PF-562-271 inhibited ligand-stimulated cell migration of most cancer cell lines tested. PF-562-271 treatment of normal fibroblasts or epithelial cells and cancer cell lines at maximal inhibitory doses failed to inhibit cell growth in tissue culture or induce apoptosis of adherent cells when used at concentrations that effectively inhibited FAK activity. However, when tumor cells were placed under conditions, of anchorage independent growth, PF-562-271 effectively blocked tumor cell growth, mimicking the effects of this drug in xenograft models. Thus cell culture and animal studies provide strong support for the use of PF-562-271 for the treatment of human malignancies. The clinical evaluation of PF-562-271 for the treatment of late stage cancers is ongoing.