Citation

Tumor chemotherapy resistance arises frequently and limits high grade serous ovarian cancer (HGSOC) patient survival. Focal adhesion kinase (FAK) is an intracellular protein-tyrosine kinase encoded by PTK2, a gene that is often gained in HGSOC. Canonically, FAK functions at the cell periphery. However, FAK also transits to the nucleus to modulate gene expression. We find that FAK is tyrosine phosphorylated and nuclear localized in HGSOC patient tumors surviving neoadjuvant platinum-paclitaxel chemotherapy and that FAK nuclear accumulation occurs upon sub-cytotoxic cisplatin exposure to ovarian tumor cells in vitro. FAK nuclear localization sequence (NLS) mutational inactivation resulted in tumor cell sensitization to cisplatin in vitro and in vivo relative to wildtype FAK reconstituted ovarian tumor cells. Cisplatin cytotoxicity was associated with elevated extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activation in FAK NLS- cells, cisplatin-stimulated ERK activation was also enhanced upon loss of FAK activity or expression, and cisplatin-stimulated cell death was prevented by an inhibitor of ERK signaling. MAPK phosphastase-1 (MKP1) negatively regulates ERK signaling and cisplatin-induced MKP1 levels were significantly elevated in FAK-WT compared to FAK-NLS- ovarian tumor cells. Notably, small molecule MKP1 inhibition enhanced both cisplatin-stimulated ERK phosphorylation and ovarian tumor cell death. Together, our results show that FAK expression, activity, and nuclear localization limit cisplatin cytotoxicity in part by regulating MKP1 levels and preventing non-canonical ERK/MAPK activation.