Abstract LB-346: EGF receptor, Jaks and Stat3 crosstalk promote enhanced colony-forming, motility, migration, and invasive phenotype of cisplatin-resistant ovarian cancer cells

Abstract

Abstract Majority of the ovarian cancer patients who initially respond to cisplatin therapy develop recurrent and resistant disease that is mechanistically not well understood. To define the biological presentations and the molecular phenotype of cisplatin resistant ovarian cancer, we subjected the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments, followed by recovery and derived the lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), which are resistant to 1, 3, and 5 μM cisplatin, respectively. In vitro studies show the three resistant lines have increased colony-forming ability and altered morphology consistent with enhanced motility, migration, and invasiveness. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase 1/2 and Janus kinases (Jaks), and aberrant Signal Transducer and Activator of Transcription (Stat) 3 activation. Elevated expression of survivin and vascular endothelial growth factor (VEGF), and enhanced matrix metalloproteinase activities are evident in the resistant cells, together with increased vimentin and snail expression, and E-cadherin downregulation, indicative of epithelial-mesenchymal transition (EMT). The inhibition of EGFR or Stat3 activity in the resistant cells repressed the enhanced colony-forming, motility, and migratory phenotype, downregulated survivin, VEGF and vimentin expression, and sensitized the resistant cells to cisplatin. In vivo studies using intra-peritoneal xenograft models in nude mice revealed the resistant lines have a high tumor incidence and formed small, cisplatin-resistant tumor nodules at several locations on the small-intestine and colon, compared to the sensitive A2780S line that exhibited low tumor incidence and formed exclusively ovarian tumors. Treatment with EGFR or Stat3 inhibitor sensitized the resistant tumor nodules to cisplatin. Studies together indicate hyperactive EGFR and Jak signaling predominantly through the induction of aberrantly-active Stat3 promote EMT during cisplatin resistance development. Collectively, these events serve as critical mediators of the invasive phenotype associated with cisplatin resistant ovarian cancer and hence, are targets for preventing the development of resistance and the recurrent disease during cisplatin therapy in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-346. doi:1538-7445.AM2012-LB-346