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Diaz Osterman CJ , Ozmadenci D , Kleinschmidt EG , Taylor KN , Barrie AM , Jiang S , 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 G , Fisch KM , Kolev VN , Weaver DT , Pachter JA , Gyorffy B , McHale MT , Connolly DC , Molinolo A , Stupack DG , Schlaepfer DD
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Elife. 2019 Sep 3;8
PMID: 31478830    PMCID: PMC6721800    URL: https://www.ncbi.nlm.nih.gov/pubmed/31478830
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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-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.
Notes
2050-084x Diaz Osterman, Carlos J Ozmadenci, Duygu Kleinschmidt, Elizabeth G Taylor, Kristin N Barrie, Allison M Jiang, Shulin Bean, Lisa M Sulzmaier, Florian J Jean, Christine Tancioni, Isabelle Anderson, Kristen Uryu, Sean Cordasco, Edward A Li, Jian Chen, Xiao Lei Fu, Guo Ojalill, Marjaana Rappu, Pekka ORCID: http://orcid.org/0000-0002-5068-2842 Heino, Jyrki Mark, Adam M Xu, Guorong Fisch, Kathleen M Kolev, Vihren N Weaver, David T Pachter, Jonathan A Gyorffy, Balazs McHale, Michael T Connolly, Denise C Molinolo, Alfredo Stupack, Dwayne G ORCID: https://orcid.org/0000-0003-4396-5745 Schlaepfer, David D ORCID: https://orcid.org/0000-0003-4814-9210 RO1 CA180769/NH/NIH HHS/United States RO1 CA102310/NH/NIH HHS/United States RO1 CA107263/NH/NIH HHS/United States T32 CA121938/NH/NIH HHS/United States P30 CA023100/NH/NIH HHS/United States UL1 TR001442/NH/NIH HHS/United States T36 GM095349/NH/NIH HHS/United States P30 CA006927/NH/NIH HHS/United States RO1 CA195723/NH/NIH HHS/United States W81XWH-16-1-0142/United States Department of Defense W81XWH-19-1-0134/United States Department of Defense NVKP_16-1-2016-0037/Medical Research Council of Hungary 2018-1.3.1-VKE-2018-00032/Medical Research Council of Hungary KH-129581/Medical Research Council of Hungary Journal Article England Elife. 2019 Sep 3;8. pii: 47327. doi: 10.7554/eLife.47327.