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FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.
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; Heino, Jyrki; Mark, Adam M; Xu, Guorong; Fisch, Kathleen M; Kolev, Vihren N; Weaver, David T; Pachter, Jonathan A; Gyorffy, Balázs; McHale, Michael T; Connolly, Denise C; Molinolo, Alfredo; Stupack, Dwayne G; Schlaepfer, David D.
Afiliação
  • Diaz Osterman CJ; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Ozmadenci D; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Kleinschmidt EG; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Taylor KN; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Barrie AM; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Jiang S; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Bean LM; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Sulzmaier FJ; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Jean C; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Tancioni I; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Anderson K; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Uryu S; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Cordasco EA; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Li J; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • Chen XL; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • Fu G; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • Ojalill M; Department of Biochemistry, University of Turku, Turku, Finland.
  • Rappu P; Department of Biochemistry, University of Turku, Turku, Finland.
  • Heino J; Department of Biochemistry, University of Turku, Turku, Finland.
  • Mark AM; Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States.
  • Xu G; Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States.
  • Fisch KM; Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States.
  • Kolev VN; Verastem Oncology, Needham, United States.
  • Weaver DT; Verastem Oncology, Needham, United States.
  • Pachter JA; Verastem Oncology, Needham, United States.
  • Gyorffy B; Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
  • McHale MT; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
  • Connolly DC; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • Molinolo A; Fox Chase Cancer Center, Philadelphia, United States.
  • Stupack DG; Department of Pathology, Moores UCSD Cancer Center, La Jolla, United States.
  • Schlaepfer DD; Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
Elife ; 82019 09 03.
Article em En | MEDLINE | ID: mdl-31478830
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-ß-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 ß-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Ovarianas / Platina / Resistencia a Medicamentos Antineoplásicos / Quinase 1 de Adesão Focal / Antineoplásicos Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Ovarianas / Platina / Resistencia a Medicamentos Antineoplásicos / Quinase 1 de Adesão Focal / Antineoplásicos Idioma: En Ano de publicação: 2019 Tipo de documento: Article