2. Academic Validation
  3. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

  • Elife. 2019 Sep 3;8:e47327. doi: 10.7554/eLife.47327.
Carlos J Diaz Osterman  # 1,  Duygu Ozmadenci  # 1,  Elizabeth G Kleinschmidt  # 1,  Kristin N Taylor  # 1,  Allison M Barrie  # 1,  Shulin Jiang  # 1,  Lisa M Bean  # 1,  Florian J Sulzmaier  # 1,  Christine Jean 1,  Isabelle Tancioni 1,  Kristen Anderson 1,  Sean Uryu 1,  Edward A Cordasco 1,  Jian Li 2,  Xiao Lei Chen 2,  Guo Fu 2,  Marjaana Ojalill 3,  Pekka Rappu 3,  Jyrki Heino 3,  Adam M Mark 4,  Guorong Xu 4,  Kathleen M Fisch 4,  Vihren N Kolev 5,  David T Weaver 5,  Jonathan A Pachter 5,  Balázs Győrffy 6 7,  Michael T McHale 1,  Denise C Connolly 8,  Alfredo Molinolo 9,  Dwayne G Stupack 1,  David D Schlaepfer 1
Affiliations

Affiliations

  • 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.
  • 2 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 3 Department of Biochemistry, University of Turku, Turku, Finland.
  • 4 Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States.
  • 5 Verastem Oncology, Needham, United States.
  • 6 Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
  • 7 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
  • 8 Fox Chase Cancer Center, Philadelphia, United States.
  • 9 Department of Pathology, Moores UCSD Cancer Center, La Jolla, United States.
  • # Contributed equally.
PMID: 31478830 DOI: 10.7554/eLife.47327
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.

Keywords

beta-catenin; cancer biology; focal adhesion kinase FAK; mouse; ovarian cancer; platinum chemotherapy; pluripotency; tumorspheres.

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