FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Carlos J. Díaz Osterman,
Elizabeth G. Kleinschmidt,
Kristin N. Taylor,
Allison M. Barrie,
Lisa M. Bean,
Florian J. Sulzmaier,
Edward A. Cordasco,
Xiao Lei Chen,
Adam M. Mark,
Kathleen M. Fisch,
Vihren N. Kolev,
David T. Weaver,
Jonathan A. Pachter,
Michael T. McHale,
Denise C. Connolly,
Dwayne G. Stupack,
David D. Schlaepfer
Posted 30 Mar 2019
bioRxiv DOI: 10.1101/594184 (published DOI: 10.7554/eLife.47327)
Posted 30 Mar 2019
Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-b-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/b-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.
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