Dataset Information

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

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).

SUBMITTER: Fraunhoffer NA

PROVIDER: S-EPMC10189188 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

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

Fraunhoffer Nicolas A NA Moreno Vega Aura I AI Abuelafia Analía Meilerman AM Morvan Marie M Lebarbier Emilie E Mary-Huard Tristan T Zimmermann Michael T MT Lomberk Gwen G Urrutia Raul R Dusetti Nelson N Blum Yuna Y Nicolle Remy R Iovanna Juan J

EBioMedicine 20230504

<h4>Background</h4>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 pancreat ...[more]

PMID: 37148583

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Dataset Information

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

Background

Methods

Findings

Interpretation

Funding

Publications

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

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