Faculty Collaboration Database

Priming therapy by targeting enhancer-initiated pathways in patient-derived pancreatic cancer cells. EBioMedicine 2023 Jun;92:104602

Date

05/06/2023

Pubmed ID

37148583

Pubmed Central ID

PMC10189188

DOI

10.1016/j.ebiom.2023.104602

Scopus ID

2-s2.0-85154565512 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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 <0.01). Furthermore, we developed a classifier using the baseline transcriptome of epidrug-primed-chemosensitized PDPCCs to predict the best epidrug-priming regime to a given chemotherapy. Six signatures with a significant association with the chemosensitization centroid (R ≤ -0.80; p-value < 0.01) were identified and validated in a subset of PDPCCs.

INTERPRETATION: We conclude that targeting enhancer-initiated pathways in patient-derived primary cells, represents a promising approach for developing new therapies for human pancreatic cancer.

FUNDING: This work was supported by INCa (Grants number 2018-078 to ND and 2018- 079 to JI), Canceropole PACA (ND), Amidex Foundation (ND), and INSERM (JI).

Author List

Fraunhoffer NA, Moreno Vega AI, Abuelafia AM, Morvan M, Lebarbier E, Mary-Huard T, Zimmermann MT, Lomberk G, Urrutia R, Dusetti N, Blum Y, Nicolle R, Iovanna J

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Pancreatic Neoplasms
Precision Medicine