Cancer Biology and Signal Transduction FAK Inhibition Disrupts a b5 Integrin Signaling Axis Controlling Anchorage-Independent Ovarian Carcinoma Growth

Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays,we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, b5 integrin, and osteopontin matrix staining. Elevated osteopontin, b5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 mmol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promotedHEY andOVCAR8G0–G1 cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 mmol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth inmice with corresponding reductions in b5 integrin and osteopontin expression. b5 knockdown reducedHEY cell growth in soft agar, tumor growth inmice, and both FAKY397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor–resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY,OVCAR8) increasedgrowthbutdidnot create a FAK inhibitor–resistant phenotype. These results link osteopontin, b5 integrin, and FAK in promoting ovarian tumor progression. b5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling.MolCancer Ther; 13(8); 2050–61. 2014 AACR.