Abstract 667: Tumor cell dormancy is mediated by an increase in RTK signaling in reversible pancreatic cancer models expressing oncogenic K-Ras and c-Myc

Abstract

Abstract Recent genetic studies of pancreatic cancer expressing mutant Kras and c-Myc strongly favor targeted therapies against these oncogenic drivers for the successful treatment of advanced staged pancreatic cancer. The potential limitation of these treatments is that they likely leave residual cancer cells that can play a role in tumor recurrence. Our study is focused on understanding the molecular mechanism of the survival of pancreatic cancer cells in the absence of the tumor-driving oncogene in order to successfully eliminate cancer cells and prevent tumor relapse. Using a reversible c-Myc-induced pancreatic cancer model, we have demonstrated that expression of c-Myc in pancreatic progenitors is sufficient to induce invasive pancreatic cancer, and its expression is required for the maintenance of tumors at primary and metastatic sites. However, despite the complete macroscopic remission of invasive pancreatic tumors at primary and metastatic sites upon downregulation of c-Myc, a few cancer cells survived and remained dormant for a protracted period of time (Lin et al., 2013). In this current study, we have used a reversible Kras-induced pancreatic tumor model and found that cancer cell dormancy is a common attribute in pancreatic cancer following oncogene ablation. In an effort to identify common, cancer cell-intrinsic molecular pathways that mediate residual disease following the ablation of oncogenic drivers, we performed a genome-wide gene expression analysis (RNA-Seq) of in vivo-derived bulk tumor cells and dormant cancer cells that survived the ablation of c-Myc and oncogenic Kras. Comparison of the gene expression profile of bulk and residual cancer cells revealed that the residual cancer cells have increased receptor tyrosine kinase (RTK)/Akt signaling as a common mechanism for their survival in both c-Myc and Kras-induced tumors. We have experimentally validated the importance of this signaling pathway in cancer cell survival in the absence of oncogenic signaling in both tumor models. In comparison to control mice, we observed a significant slow tumor growth and delayed tumor relapse resulting in longer survival of the tumor bearing mice though a combination of this RTK/Akt pathway inhibition and ablation of Kras or c-Myc. In conclusion, our current study in reversible cancer models highlights the importance for the development of an adjuvant therapeutic strategy targeting this RTK/Akt pathway in addition to oncogenic drivers to effectively eradicate residual cancer cells and to prevent pancreatic cancer recurrence. Citation Format: Nirakar Rajbhandari. Tumor cell dormancy is mediated by an increase in RTK signaling in reversible pancreatic cancer models expressing oncogenic K-Ras and c-Myc. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 667.