Focal adhesion kinase: An alternative focus for anti-angiogenesis therapy in ovarian cancer

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

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAKY397 were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRTPCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P < 0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P < 0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P < 0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.

Original languageEnglish (US)
Pages (from-to)919-929
Number of pages11
JournalCancer Biology and Therapy
Volume15
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Angiogenesis
  • Cancer/molecular biology
  • Metastasis
  • Targeted therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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    Stone, R. L., Baggerly, K. A., Armaiz-Pena, G. N., Kang, Y., Sanguino, A. M., Thanapprapasr, D., Dalton, H. J., Bottsford-Miller, J., Zand, B., Akbani, R., Diao, L., Nick, A. M., DeGeest, K., Lopez-Berestein, G., Coleman, R. L., Lutgendorf, S., & Sood, A. K. (2014). Focal adhesion kinase: An alternative focus for anti-angiogenesis therapy in ovarian cancer. Cancer Biology and Therapy, 15(7), 919-929. https://doi.org/10.4161/cbt.28882