Abstract C028: GSK3β: a therapeutic target in KRAS mutant pancreatic cancers

Abstract Glycogen synthase kinase-3beta (GSK3β) is a multifunctional serine/threonine kinase seen at the convergence of several signaling cascades. GSK3β plays a central role in PI3K signaling and Wnt/beta-catenin signaling pathways, which are the key regulators of important biological functions like cell growth, survival, metabolism, epithelial–mesenchymal transition (EMT), cell proliferation and differentiation at various stages of embryonic and adult development. Accordingly, dysregulation of GSK3β has been linked to pathogenesis of cancer, diabetes, and several neurodegenerative disorders. Therefore, pharmacological interventions to inhibit GSK3β activity is an important therapeutic strategy to counter these abnormalities. Previously, we identified a highly selective, with a better pharmacokinetic profile pyrimidinylazaindole based small molecule inhibitor of GSK3β that showed potent growth inhibition in cell based and xenograft models of KRas mutant pancreatic cancers. Pertinently, this small molecule inhibitor was seen to induce apoptosis in a β-catenin and c-Myc dependent manner. Moreover, GSK3β inhibition decreased the nuclear activity of the NF-kB p65 in KRas mutated MiaPaCa-2 cells thereby impeding the cell survival and anti-apoptotic processes in these cells as well as in the xenograft model of pancreatic cancer. Since EMT driven chemoresistance remains one of the important factors involved in pancreatic cancer progression. Overcoming drug resistance in pancreatic cancer patients poses a prominent challenge, predominantly in cancers driven by K-RAS mutation. Here in this study, we have shown that small molecule inhibitor imapacts the EMT progresson in KRAS mutant pancreatic caners through mediating significant decreases in EMT markers like N Cadherins, and slug. No detectable levels of E-cadherin were seen, however, vimentin, ZEB and snail remained unchanged. While the recently FDA approved GSK3β inhibitor, elraglusib, inhibits both alpha and beta isoforms equally and shows relatively higher half maximal inhibitory concentration however, small mole identified in our study would prove a clinically-relevant choice for its higher potency, bioavailability, pharmacokinetic and drug like properties however further analysis. This study opens up new avenues for therapeutic treatment of mutant KRas-dependent human cancers through pharmacological inhibition of GSK3β. Citation Format: MIR OWAIS AYAZ, MOHD JAMAL DAR JAMAL. DAR. GSK3β: a therapeutic target in KRAS mutant pancreatic cancers abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr C028.