Coordinate Translational Control Of The Kras Signaling Pathway

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 multiple GQ elements in the 59UTRs of mRNAs encoding KRAS and key downstream signalling 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 pharmacological inhibitors. We find that KRAS and downstream signalling 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. CR31B is a silvestrol analogue that efficiently and selectively blocks eIF4A. CR31B kills PDAC cells at nanomolar concentrations and has significant single agent in vivo efficacy across xenograft, primary PDX, and murine models of PDAC. Together, our findings reveal coordinate, GQ- and eIF4A-mediated control of the translation of key RAS signalling molecules as a vulnerability in KRAS-driven pancreatic cancer. Citation Format: Kamini Singh, Jianan Lin, Nicolas Lecomte, Prathibha Mohan, Steve D. Leach, Zhengqing Ouyang, Hans-Guido Wendel. Coordinate translational control of the kras signaling pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1824.