Priming therapy by targeting enhancer-initiated pathways in patient-derived pancreatic cancer cells
Year: 2023
Type: article
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: 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).
Source: EBioMedicine
Institutions: Centre National de la Recherche Scientifique, Consejo Nacional de Investigaciones Científicas y Técnicas, Inserm, Aix-Marseille Université, Universidad de Buenos Aires, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, La Ligue Contre le Cancer, Université Paris Nanterre, Modélisation aléatoire de Paris Nanterre, AgroParisTech, Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Mathématiques et Informatique Appliquées, Génétique Quantitative et Évolution Le Moulon, Medical College of Wisconsin, Institut de génétique et de développement de Rennes, Université de Rennes, Université Paris Cité, Centre de Recherche sur l'Inflammation, Hospital El Cruce
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,000
OpenAlex ID: W4368368544