1. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.
- Author
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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, Győrffy B, McHale MT, Connolly DC, Molinolo A, Stupack DG, and Schlaepfer DD
- Subjects
- Animals, Cisplatin pharmacology, Disease Models, Animal, Female, Humans, Mice, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Signal Transduction, Stem Cells, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Focal Adhesion Kinase 1 metabolism, Ovarian Neoplasms drug therapy, Platinum pharmacology
- 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 K ras , M yc and F AK (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., Competing Interests: CD, DO, EK, KT, AB, SJ, LB, FS, CJ, IT, KA, SU, EC, JL, XC, GF, MO, PR, JH, AM, GX, KF, BG, MM, DC, AM, DS, DS No competing interests declared, VK Former employee at Verastem Inc, DW, JP employee of Verastem Inc, (© 2019, Diaz Osterman et al.)
- Published
- 2019
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