Abstract
Abstract The frequent occurrence of Myc deregulation in human cancers makes Myc an intriguing potential therapeutic target. This is supported by recent studies demonstrating 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. In the case of insulinoma, regression is presaged by collapse of the tumor microenvironment and involution of the tumor vasculature. One feature of human pancreatic ductal adenocarcinoma (PDAC) is its extensive stromal component (desmoplasia) that is thought to contribute to the resistance of PDAC to current therapies. We show that systemic Myc inhibition in the well-established KRasG12D-driven PDAC mouse model 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, ectopic expression of physiological levels of deregulated Myc enhances pancreatic tumor progression and drives stromal desmoplasia, and this reverses upon cessation of deregulated Myc. That systemic Myc inhibition causes regression of both tumor and its associated stroma, while ectopic activation of Myc in tumor cells drives both tumor progression and desmoplasia, confirm that Myc 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, Laura Soucek, Trevor D. Littlewood, 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 Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A52.
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