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Priming therapy by targeting enhancer-initiated pathways in patient-derived pancreatic cancer cells
Nicolas A Fraunhoffer1, Aura I Moreno Vega2, Analía Meilerman Abuelafia3
1Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France; Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina.
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).
Insights
This study explores using epigenomic inhibitors (epidrugs) to sensitize pancreatic cancer cells to chemotherapy. Targeting enhancer pathways shows promise for new pancreatic cancer therapies.
Area of Science:
- Oncology
- Systems Biology
- Genomics
Background:
- Precision oncology utilizes multi-omics and chemogenomics for targeted therapies.
- Epigenomic inhibitors (epidrugs) can reprogram gene expression in cancer cells.
- Pancreatic cancer remains a challenging malignancy with limited treatment options.
Purpose of the Study:
- To investigate the efficacy of epidrugs in sensitizing pancreatic cancer cells to chemotherapy.
- To explore the potential of epidrugs in resetting gene expression patterns driving pancreatic cancer.
- To develop a predictive classifier for optimal epidrug-chemotherapy combinations.
Main Methods:
- Tested ten epidrugs targeting enhancer regulators on 17 patient-derived primary pancreatic cancer cell cultures (PDPCCs).
- Assessed epidrugs' ability to sensitize PDPCCs to five standard chemotherapeutic drugs.
- Analyzed transcriptomic changes induced by epidrugs and developed a predictive classifier.
Main Results:
- Activating epidrugs significantly upregulated more genes than repressive epidrugs (p<0.01).
- A classifier was developed to predict effective epidrug-chemotherapy regimens based on baseline transcriptomes.
- Six gene signatures associated with chemosensitization were identified and validated (R≤-0.80, p<0.01).
Conclusions:
- Targeting enhancer-initiated pathways with epidrugs is a promising strategy for pancreatic cancer therapy.
- This chemogenomic approach offers a novel avenue for developing personalized pancreatic cancer treatments.
- Further research into epidrugs could lead to improved patient responses and outcomes.
