A targetable co-dependence of PI3Kα/δ and SUMO signaling in aggressive pancreatic cancer

ABSTRACT: The phosphatidylinositol-3-kinase (PI3K) signaling pathway plays a critical role in the biology and aggressive course of pancreatic ductal adenocarcinoma (PDAC), yet pharmacological PI3K targeting has not resulted in meaningful clinical success. Through genetic and pharmacological screenings, we identified a targetable co-dependence between PI3K and the small ubiquitin-like modifier (SUMO) pathway in PDAC. Simultaneous inhibition of PIK3α and PIK3δ, combined with SUMO-activating E1 targeting, triggered synthetic lethality and an immunogenic cell death phenotype in preclinical models. In syngeneic orthotopic immune-competent PDAC models, this combination therapy reduced tumor growth and promoted T cell infiltration, signaling a strong antitumor response. The PI3Kα/δ and SUMO targeting approach thus shows potential for clinical translation and could form the basis for more effective therapies in PDAC, a cancer with significant unmet medical needs. This study introduces a combination therapy targeting the PI3K pathway and the SUMOylation pathway in pancreatic cancer. Combined PI3K and SUMOylation inhibition reveals preclinical efficacy including immune-modulatory effects in multiple pancreatic cancer models. The proposed combination therapy has the potential to provide transformative clinical benefits for pancreatic cancer patients.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Pancreas

DISEASE(S): Pancreatic Cancer

SUBMITTER: Marieluise Kirchner  

LAB HEAD: Philipp Mertins

PROVIDER: PXD059116 | Pride | 2026-02-22

REPOSITORIES: Pride