Abstract 3000: Targeting ERK and PI3K signaling in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a dismal five-year survival rate of only 13%. The high mortality is largely due to late-stage diagnosis, limited surgical options (available in just 10-20% of cases), and the failure of current chemotherapy regimens, which are often plagued by toxicity and drug resistance. Therefore, innovative therapeutic strategies targeting key signaling pathways driving tumor progression are urgently needed. Mutations in the KRAS gene, present in approximately 95% of PDAC cases, lead to hyperactivation of the KRAS protein and downstream pathways, including extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K). In this study, we hypothesized that simultaneous inhibition of these critical pathways could effectively suppress PDAC cell proliferation. Using SCH772984 (an ERK 1/2 inhibitor) and pictilisib (a class I PI3K inhibitor), we evaluated their combined effects on human PDAC cell lines (MIA PaCa-2 and PANC-1) and a patient-derived xenograft (PDX) cell line. Our results demonstrate significant synergy between these two inhibitors, as evidenced by reduced cell viability and colony formation in clonogenic assays compared to single-agent treatments. Western blot analysis confirmed that SCH772984 was able to inhibit its target ERK 1/2 and pictilisib was able to inhibit AKT, that is downstream of PI3K. These findings suggest that dual targeting of ERK and PI3K pathways effectively disrupts PDAC cell growth. Future studies will focus on formulating these inhibitors into nanoparticle-based drug delivery systems to enhance solubility, stability, and tumor-specific delivery. Additionally, preclinical testing in animal models will provide critical insights into the therapeutic potential of this combination. This approach represents a promising avenue for improving PDAC treatment outcomes and addressing unmet needs in this aggressive disease. Citation Format: Gauthami Nair, Katie Reindl, Mohiuddin Quadir. Targeting ERK and PI3K signaling in 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 3000.