Abstract PHA03: Coordinate translational control of KRAS signaling pathway in pancreatic adenocarcinoma

Abstract

Abstract G-quadruplex (GQ) elements are conserved translational control elements that induce a requirement for RNA helicase activity for efficient mRNA translation. Computational structure analyses identify GQ elements in the 5´UTRs of mRNAs encoding KRAS and key downstream signaling molecules. KRAS is a key oncogene in pancreatic ductal adenocarcinoma (PDAC) and many other cancers, and except for the specific G12C KRAS mutation we do not have pharmacologic inhibitors. We find that KRAS and downstream signaling molecules, including PI3K, RALA, RAC2, MYC, MET, and YAP1, strictly depend on the RNA helicase eIF4A for their translation. This implies a potential utility for eIF4A/DDX2 inhibitors such as the silvestrol analogue CR31B. Indeed, CR31B shows nanomolar cell kill in vitro and in vivo efficacy across xenograft, primary PDX, and murine PDAC models. Together, our study reveals a signature of coordinate and eIF4A/DDX2 dependent oncogene translation in PDAC that is potentially accessible to therapeutic attack. This abstract is also being presented as Poster A18. Citation Format: Kamini Singh, Hans-Guido Wendel. Coordinate translational control of KRAS signaling pathway in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA03.