UC San Diego

Ovarian cancer is one of the deadliest cancers affecting women worldwide. Platinum with paclitaxel chemotherapy after surgery is standard of care. However, ~80% of patients will recur and eventually develop chemotherapy resistance with few approved treatment options. In both high grade serous ovarian cancer (HGSOC) and murine models of ovarian cancer, elevated focal adhesion kinase (FAK) expression is common and increased FAK tyrosine phosphorylation has been linked to adaptive chemotherapy resistance. Herein, I present results that cisplatin but not paclitaxel chemotherapy increases FAK tyrosine phosphorylation and nuclear accumulation as evaluated by cell fractionation, immunofluorescent cell staining, and immunoblotting. To create a model to test FAK nuclear function, FAK knockout ovarian tumor cells were reconstituted with green fluorescent fusion proteins of FAK wildtype (WT) or a N-terminal domain-containing point mutations (R177A R178A, NLS-) of FAK disrupting a known nuclear localization sequence. Both FAK WT and FAK NLS- grow equivalently in cell culture and 20 µM cisplatin for 12 hours (IC50 concentration for cell death) triggered FAK WT but not FAK NLS- nuclear accumulation with increased apoptosis occurring in FAK NLS- compared to FAK-WT cells. FAK-WT expression promoted cisplatin resistance compared to FAK NLS- whereas sensitivity to paclitaxel was equivalent. FAK-WT and FAK NLS- grew equivalently as control orthotopic tumors in mice whereas cisplatin treatment (2 mg/kg, weekly) significantly prevented FAK NLS- tumor growth compared to FAK-WT tumors. These results show that intrinsic FAK nuclear localization within ovarian tumor cells is associated with resistance to cisplatin-mediated cell death in vitro and in vivo. Ongoing studies are focused on unraveling cell survival signal(s) associated with nuclear FAK.