Pathway2Targets: an open-source pathway-based approach to repurpose therapeutic drugs and prioritize human targets

Abstract

Background Recent efforts to repurpose existing drugs to different indications have been accompanied by a number of computational methods, which incorporate protein-protein interaction networks and signaling pathways, to aid with prioritizing existing targets and/or drugs. However, many of these existing methods are focused on integrating additional data that are only available for a small subset of diseases or conditions. Methods We have designed and implemented a new R-based open-source target prioritization and repurposing method that integrates both canonical intracellular signaling information from five public pathway databases and target information from public sources including OpenTargets.org. The Pathway2Targets algorithm takes a list of significant pathways as input, then retrieves and integrates public data for all targets within those pathways for a given condition. It also incorporates a weighting scheme that is customizable by the user to support a variety of use cases including target prioritization, drug repurposing, and identifying novel targets that are biologically relevant for a different indication. Results As a proof of concept, we applied this algorithm to a public colorectal cancer RNA-sequencing dataset with 144 case and control samples. Our analysis identified 430 targets and ~700 unique drugs based on differential gene expression and signaling pathway enrichment. We found that our highest-ranked predicted targets were significantly enriched in targets with FDA-approved therapeutics for colorectal cancer (p-value < 0.025) that included EGFR, VEGFA, and PTGS2. Interestingly, there was no statistically significant enrichment of targets for other cancers in this same list suggesting high specificity of the results. We also adjusted the weighting scheme to prioritize more novel targets for CRC. This second analysis revealed epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), and two mitogen-activated protein kinases (MAPK14 and MAPK3). These observations suggest that our open-source method with a customizable weighting scheme can accurately prioritize targets that are specific and relevant to the disease or condition of interest, as well as targets that are at earlier stages of development. We anticipate that this method will complement other approaches to repurpose drugs for a variety of indications, which can contribute to the improvement of the quality of life and overall health of such patients.

Secondary Analysis of Human Bulk RNA-seq Dataset Suggest Potential Mechanisms and Transcriptional Biomarkers for Letrozole Resistance in Estrogen Positive (ER+) Breast Cancer

“…The Pathway2Targets algorithm was then used to predict and prioritize relevant therapeutic targets from the transcriptomics signatures that could be repurposed in the case of Letrozole resistance, similar to prior work [34][35][36][37]. Briefly, this algorithm identifies known drug targets within each of the significant signaling pathways.…”