Abstract 3919: Identifying dual inhibitions of kinases to treat pancreatic ductal adenocarcinoma

Abstract Significant advancements have been achieved in elucidating the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) through the development and application of mammalian models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, we established a Drosophila model recapitulating the genetic signature of PDAC, characterized by alterations in KRAS, TP53, CDKN2A, and SMAD4, which are associated with the poorest patient prognosis. The ‘4-hit’ flies manifested tumorigenic phenotypes, such as epithelial transformation and reduced animal viability. Comprehensive kinome-wide genetic screening using this model identified potential therapeutic targets, including MEK, AURKB, and GSK3β. Notably, combined inhibition of these targets effectively suppressed the growth of human PDAC xenografts in mice. Moreover, the activity of these kinases correlated with adverse outcomes in PDAC patients. This Drosophila-based platform offers a robust whole-body assay to complement existing methodologies to determine therapeutic targets in PDAC. Citation Format: Masahiro Sonoshita. Identifying dual inhibitions of kinases to treat pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3919.