Signature Search Polestar: a comprehensive drug repurposing method evaluation assistant for customized oncogenic signature

Abstract

Abstract Summary The burgeoning high-throughput technologies have led to a significant surge in the scale of pharmacotranscriptomic datasets, especially for oncology. Signature search methods (SSMs), utilizing oncogenic signatures formed by differentially expressed genes through sequencing, have been instrumental in anti-cancer drug screening and identifying mechanisms of action without relying on prior knowledge. However, various studies have found that different SSMs exhibit varying performance across pharmacotranscriptomic datasets. In addition, the size of the oncogenic signature can also significantly impact the result of drug repurposing. Therefore, finding the optimal SSMs and customized oncogenic signature for a specific disease remains a challenge. To address this, we introduce Signature Search Polestar (SSP), a webserver integrating the largest pharmacotranscriptomic datasets of anti-cancer drugs from LINCS L1000 with five state-of-the-art SSMs (XSum, CMap, GSEA, ZhangScore, XCos). SSP provides three main modules: Benchmark, Robustness, and Application. Benchmark uses two indices, Area Under the Curve and Enrichment Score, based on drug annotations to evaluate SSMs at different oncogenic signature sizes. Robustness, applicable when drug annotations are insufficient, uses a performance score based on drug self-retrieval for evaluation. Application provides three screening strategies, single method, SS_all, and SS_cross, allowing users to freely utilize optimal SSMs with tailored oncogenic signature for drug repurposing. Availability and implementation SSP is free at https://web.biotcm.net/SSP/. The current version of SSP is archived in https://doi.org/10.6084/m9.figshare.26524741.v1, allowing users to directly use or customize their own SSP webserver.