Abstract 2528: Enhanced sensitivity of pancreatic cancer cells to the concurrent inhibition of aberrant Stat3 and EGFR or Src

Abstract

Abstract Pancreatic cancer is a lethal disease with little understanding of the etiology and no effective therapies. While aberrant epidermal growth factor receptor (EGFR), Src and Stat3 are detected in pancreatic cancer and implicated in the disease, their exact roles in the support of the disease phenotype remain poorly defined. Moreover, the potential for a cross-talk between EGFR, Src and Stat3 poses a challenge to any therapy that targets only one of these entities. In this study, we sought to define the EGFR, Src and Stat3 signaling integration and to investigate the contributory roles of the three entities to the pancreatic cancer phenotype. We found in Panc-1 and Colo-357 lines that phospho-Y845EGFR, pY1068EGFR and pY1086EGFR levels are responsive to c-Src inhibition, in contrast to pY1173EGFR that is solely EGFR kinase-dependent. Treatment of Panc-1 and Colo-357 cells with the EGFR inhibitor, Iressa (ZD 1839) or the Src inhibitor, Dasatinib (Das) suppressed the constitutively-active Stat3 activity, suggesting that both EGFR and Src activities promote aberrant Stat3 activation in pancreatic cancer cells. However, the early suppression of aberrantly-active Stat3 by the EGFR and Src inhibition in Panc-1 cells is countered by a Janus kinase (Jaks)-dependent re-activation, suggesting that Jaks activity could represent a compensatory mechanism for Stat3 induction. The abrogation of c-Src activity by either Das treatment or the over-expression of a kinase-dead c-Src mutant suppressed the levels of phospho-FAK, phospho-p130Cas, phospho-cortactin, phospho-p120catenin, and phospho-paxillin, suggesting that Src activity induces the mediators of motility and migration in pancreatic cancer cells. By contrast, neither EGFR nor Src inhibition modulated the baseline enhanced phospho-ErkMAPK or phospho-Akt levels in Panc-1 and Colo-357 cells, consistent with the observation that the inhibition of EGFR or Src alone only weakly suppressed cell growth and survival of pancreatic cancer cells. By contrast, the concurrent inhibition of Stat3 and EGFR or Src induced greater viability loss and apoptosis, and diminished the migration/invasion of pancreatic cancer cells in vitro. Of therapeutic significance, the concurrent inhibition of Stat3 and EGFR or Src, as compared to mono-targeting modality, induced a stronger human pancreatic tumor growth inhibition in xenografts models. We infer that the large tumor growth inhibition in vivo is due to the simultaneous suppression of the abnormal functions of Stat3 and EGFR or Src. These studies strongly suggest that the concurrent targeting of Stat3 and EGFR or Src could be a beneficial therapeutic approach for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2528.