A1 Refereed original research article in a scientific journal
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Authors: Osterman CJD, Ozmadenci D, Kleinschmidt EG, Taylor KN, Barrie AM, Jiang SL, Bean LM, Sulzmaier FJ, Jean C, Tancioni I, Anderson K, Uryu S, Cordasco EA, Li J, Chen XL, Fu G, Ojalill M, Rappu P, Heino J, Mark AM, Xu GR, Fisch KM, Kolev VN, Weaver DT, Pachter JA, Gyorffy B, McHale MT, Connolly DC, Molinolo A, Stupack DG, Schlaepfer DD, Schlaepfer DD
Publisher: ELIFE SCIENCES PUBLICATIONS LTD
Publication year: 2019
Journal: eLife
Journal name in source: ELIFE
Journal acronym: ELIFE
Article number: ARTN e47327
Volume: 8
Number of pages: 34
ISSN: 2050-084X
eISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.47327
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/42614756
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-beta-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (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 beta-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.
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