FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31478830.
- Also identified by DOI 10.7554/eLife.47327 and PMC identifier 6721800.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in <i><u>K</u>ras</i>, <i><u>M</u>yc</i> and <i><u>F</u>AK</i> (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.
Medical subject headings
- Antineoplastic Agents
- Drug Resistance, Neoplasm
- Focal Adhesion Kinase 1
- Ovarian Neoplasms
- Platinum