TY - JOUR
T1 - Focal adhesion kinase
T2 - An alternative focus for anti-angiogenesis therapy in ovarian cancer
AU - Stone, Rebecca L.
AU - Baggerly, Keith A.
AU - Armaiz-Pena, Guillermo N.
AU - Kang, Yu
AU - Sanguino, Angela M.
AU - Thanapprapasr, Duangmani
AU - Dalton, Heather J.
AU - Bottsford-Miller, Justin
AU - Zand, Behrouz
AU - Akbani, Rehan
AU - Diao, Lixia
AU - Nick, Alpa M.
AU - DeGeest, Koen
AU - Lopez-Berestein, Gabriel
AU - Coleman, Robert L.
AU - Lutgendorf, Susan
AU - Sood, Anil K.
N1 - Funding Information:
The authors thank Robert R. Langley and Donna Reynolds for helpful discussions and assistance with immunohistochemistry. We would also like to recognize Nicolas Jennings who provided technical expertise in the execution of laboratory experiments. R.L.S., J.B.M., and B.Z. are supported by the NCI T32 Training Grant (CA101642). This research was funded in part by support from NIH Grants (CA110793 and CA109298), the U.T. MD Anderson Cancer Center Ovarian Cancer Spore (P50 CA083639), the Zarrow Foundation, the Betty Ann Asche Murray Distinguished Professorship and the Marcus Foundation to A.K.S., the Ann Rife Cox Chair in Gynecology to R.L.C., and NIH Grants CA-104825 and CA-140933 to S.K.L.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Cancer/molecular biology
KW - Metastasis
KW - Targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=84903852837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903852837&partnerID=8YFLogxK
U2 - 10.4161/cbt.28882
DO - 10.4161/cbt.28882
M3 - Article
C2 - 24755674
AN - SCOPUS:84903852837
SN - 1538-4047
VL - 15
SP - 919
EP - 929
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 7
ER -