Targeting Mutual Dependence of Phosphatidylinositol-3-Kinase α/δ and Small Ubiquitin-Like Modifier Signaling in Pancreatic Cancer

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer, with a 5-year survival rate of <13%. Despite advances in diagnostics and treatments, the standard of care for PDAC remains inadequate, and most patients develop resistance to therapy. Targeted approaches, such as Kirsten rat sarcoma (KRAS) inhibition, have shown promise in preclinical models, although clinical application remains challenged by the rapid development of resistance. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is critical for PDAC development and maintenance, yet pharmacologic targeting has failed to yield significant clinical benefits. Methods: To investigate the relationship between the PI3K and small ubiquitin-like modifier (SUMO) pathways in PDAC, we used a comprehensive approach that included unbiased genome-wide clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 resistance screens, pharmacologic screens, transcriptomics, proteomics, and phosphoproteomics experiments. Genetic knockout models were applied to validate our findings. A novel molecularly targeted combination therapy was tested in preclinical mouse models. Results: Using genetic and pharmacologic screenings, we discovered a mutual and targetable codependence between the PI3K and the SUMO pathways. Simultaneous inhibition of PIK3α and PIK3δ, combined with SUMO-activating E1 targeting, triggered synthetic lethality and cell death. In syngeneic orthotopic immune-competent PDAC models, this combination therapy reduced tumor growth and promoted immune cell infiltration and activity. Conclusions: Our study introduces a novel rational combination therapy in PDAC. Dual targeting of PI3Kα/δ and SUMO signaling bears potential for clinical translation.