Abstract B09: Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment

Abstract

Abstract Deregulation of Myc is observed in most, if not all, human cancers making it an attractive therapeutic target. Indeed, recent studies demonstrate that Myc inhibition (via expression of a dominant negative Myc mutant) triggers regression of SV40-driven pancreatic islet tumors and KRasG12D-driven lung tumors in mice. Myc inhibition in insulinomas elicits regression presaged by collapse of the tumor microenvironment and involution of the tumor vasculature. A characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) is an extensive stromal component (desmoplasia) that is thought to contribute to the resistance of PDAC to current therapies. We show that systemic Myc inhibition in KRasG12D-driven mouse PDAC triggers regression of both tumor and its associated desmoplastic stroma, indicating that endogenous Myc function in the tumor cells is required for maintenance of the desmoplastic reaction. Consistent with this, deregulated expression of physiological levels of Myc enhances pancreatic tumor progression and promotes local immune evasion and stromal desmoplasia. Reversal of deregulated Myc activity results in reversion of these features indicating that they are dependent on Myc activity. The ubiquity of Myc in tumor development and maintenance indicates that it serves an essential and non-redundant role, coupling diverse intracellular oncogenic pathways to the tumor microenvironment, and underscoring its credentials as a pharmacological target in cancers driven by different oncogenes and arising in different tissues. Citation Format: Nicole M. Sodir, Lamorna Brown Swigart, Roderik M. Kortlever, Trevor D. Littlewood, Laura Soucek, Mark J. Arends, Gerard I. Evan. Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B09.