Diaz Osterman, Carlos J and Ozmadenci, Duygu and Kleinschmidt, Elizabeth G and Taylor, Kristin N and Barrie, Allison M and Győrffy, Balázs (2019) FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy. ELIFE, 8. ISSN 2050-084X
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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 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 β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance. © 2019, Diaz Osterman et al.
| Item Type: | Article |
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| Additional Information: | Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China Department of Biochemistry, University of Turku, Turku, Finland Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States Verastem Oncology, Needham, United States Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary Fox Chase Cancer Center, Philadelphia, United States Department of Pathology, Moores UCSD Cancer Center, La Jolla, United States Export Date: 25 September 2019 |
| Uncontrolled Keywords: | MOUSE; beta-catenin; Ovarian cancer; pluripotency; Platinum chemotherapy; cancer biology; tumorspheres; focal adhesion kinase FAK; |
| Subjects: | R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia R Medicine / orvostudomány > RJ Pediatrics / gyermekgyógyászat |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 28 Nov 2019 21:29 |
| Last Modified: | 28 Nov 2019 21:29 |
| URI: | http://real.mtak.hu/id/eprint/103961 |
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