ArticleCancer research communications2024
Nuclear Focal Adhesion Kinase Protects against Cisplatin Stress in Ovarian Carcinoma.
Article in Cancer research communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Loss of endothelial cell FAK represses cisplatin-induced vascular senescence in distal niches to reduce lung metastatic burden.Research square · 2026Article
- Disarming cancer resistance: FAK as a therapeutic target.Trends in cancer · 2026Review
- FAK inhibition in ovarian cancer releases omega-3 fatty acids to program CXCL13-producing anti-tumor resident peritoneal macrophages.Cell reports · 2026Article
- Review
- Review
- Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy.bioRxiv : the preprint server for biology · 2025Article
- Integrative multi-omics and experimental analyses implicate PTK2 as a lorazepam-associated biomarker and potential therapeutic target in ovarian cancer.Frontiers in pharmacology · 2025Article
- Novel FAK inhibitors suppress tumor growth and reverse EGFR-TKI resistance in non-small cell lung cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Article
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Authors and funding
15 authors.
Funding
Abstract
abstractTumor 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 tumors of patients with HGSOC surviving neoadjuvant platinum–paclitaxel chemotherapy and that FAK nuclear accumulation occurs upon subcytotoxic 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 wild-type FAK-reconstituted ovarian tumor cells. Cisplatin cytotoxicity was associated with elevated ERK 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 wild-type FAK compared with 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 noncanonical ERK/MAPK activation. SIGNIFICANCE: FAK inhibitors are in combinatorial clinical testing with agents that prevent Ras-Raf-MAPK pathway activation in various cancers. This study suggests that nuclear FAK limits ERK/MAPK activation in supporting HGSOC cell survival to cisplatin stress. Overall, it is likely that targets of FAK-mediated survival signaling may be tumor type- and context-dependent.
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