Priming therapy by targeting enhancer-initiated pathways in patient-derived pancreatic cancer cells

FRAUNHOFFER NICOLAS A.; MORENO VEGA, AURA I.; ABUELAFIA, ANALIA MEILERMAN; MORVAN, MARIE; LEBARBIER, EMILIE; MARY-HUARD, TRISTAN; ZIMMERMANN, MICHAEL; LOMBERK, GWEN; URRUTIA, RAUL; DUSETTI, NELSON; NICOLLE, RÉMY; IOVANNA, JUAN

eBioMedicine

Elsevier B.V.

Año: 2023 vol. 92

Background Systems biology leveraging multi-OMICs technologies, is rapidly advancing development of precision therapies and matching patients to targeted therapies, leading to improved responses. A new pillar of precision oncology lies in the power of chemogenomics to discover drugs that sensitizes malignant cells to other therapies. Here, we test a chemogenomic approach using epigenomic inhibitors (epidrugs) to reset patterns of gene expression driving the malignant behavior of pancreatic tumors. Methods We tested a targeted library of ten epidrugs targeting regulators of enhancers and super-enhancers on reprogramming gene expression networks in seventeen patient-derived primary pancreatic cancer cell cultures (PDPCCs), of both basal and classical subtypes. We subsequently evaluated the ability of these epidrugs to sensitize pancreatic cancer cells to five chemotherapeutic drugs that are clinically used for this malignancy. Findings To comprehend the impact of epidrug priming at the molecular level, we evaluated the effect of each epidrugs at the transcriptomic level of PDPCCs. The activating epidrugs showed a higher number of upregulated genes than the repressive epidrugs (χ2 test p-value