Abstract
BACKGROUND: Prioritizing candidate drugs based on genome-wide expression data is an emerging approach in systems pharmacology due to its holistic perspective for preclinical drug evaluation. In the current study, a network-based approach was proposed and applied to prioritize plant polyphenols and identify potential drug combinations in breast cancer. We focused on MEK5/ERK5 signalling pathway genes, a recently identified potential drug target in cancer with roles spanning major carcinogenesis processes. RESULTS: By constructing and identifying perturbed protein-protein interaction networks for luminal A breast cancer, plant polyphenols and drugs from transcriptome data, we first demonstrated their systemic effects on the MEK5/ERK5 signalling pathway. Subsequently, we applied a pathway-specific network pharmacology pipeline to prioritize plant polyphenols and potential drug combinations for use in breast cancer. Our analysis prioritized genistein among plant polyphenols. Drug combination simulations predicted several FDA-approved drugs in breast cancer with well-established pharmacology as candidates for target network synergistic combination with genistein. This study also highlights the concept of target network enhancer drugs, with drugs previously not well characterised in breast cancer being prioritized for use in the MEK5/ERK5 pathway in breast cancer. CONCLUSION: This study proposes a computational framework for drug prioritization and combination with the MEK5/ERK5 signaling pathway in breast cancer. The method is flexible and provides the scientific community with a robust method that can be applied to other complex diseases.