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

Elife. 2019 Sep 3;8:e47327. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cisplatin / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Female
  • Focal Adhesion Kinase 1 / metabolism*
  • Humans
  • Mice
  • Ovarian Neoplasms / drug therapy*
  • Platinum / pharmacology*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction
  • Stem Cells

Substances

  • Antineoplastic Agents
  • KRAS protein, human
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Platinum
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Cisplatin

Associated data

  • SRA/SRP194638
  • GEO/GSE129099