Unbiased discovery of cancer pathways and therapeutics using Pathway Ensemble Tool and Benchmark

Abstract

Correctly identifying perturbed biological pathways is a critical step in uncovering basic disease mechanisms and developing much-needed therapeutic strategies. However, whether current tools are optimal for unbiased discovery of relevant pathways remains unclear. Here, we create "Benchmark" to critically evaluate existing tools and find that most function sub-optimally. We thus develop the "Pathway Ensemble Tool" (PET), which outperforms existing methods. Deploying PET, we identify prognostic pathways across 12 cancer types. PET-identified prognostic pathways offer additional insights, with genes within these pathways serving as reliable biomarkers for clinical outcomes. Additionally, normalizing these pathways using drug repurposing strategies represents therapeutic opportunities. For example, the top predicted repurposed drug for bladder cancer, a CDK2/9 inhibitor, represses cell growth in vitro and in vivo. We anticipate that using Benchmark and PET for unbiased pathway discovery will offer additional insights into disease mechanisms across a spectrum of diseases, enabling biomarker discovery and therapeutic strategies.The pathogenesis of complex diseases is often underpinned by dysregulation of several cellular pathways. This is well exemplified by neoplastic diseases, where abnormalities in multiple pathways contribute to cancerous transformation or in which cancer-disposing events perturb multiple cellular pathways. Despite notable successes in some cancers, limited therapeutic gains have been made by identification and targeting of single contributory genes. Precisely pinpointing key dysregulated celluar pathways in cancer and ranking