OP0019 DEFINING SYSTEMIC LUPUS ERYTHEMATOSUS MOLECULAR TAXONOMY THROUGH DATA-DRIVEN RESTRATIFICATION AND IDENTIFICATION OF CLUSTER-TAILORED DRUGS FOR A PERSONALIZED MEDICINE APPROACH

Background: Systemic Lupus Erythematosus (SLE) is characterized by lack of treatment diversity, largely empirical treatment decisions, and paucity of novel compound development. Objectives: We sought to stratify SLE patients based on their molecular phenotype and predict personalized therapeutic compounds, tailored to the molecular fingerprint of each subgroup. Methods: We performed a co-expression analysis using our publicly available whole blood RNA-seq data of 120 SLE patients. Modules of commonly regulated genes were established and used to re-stratify patients through hierarchical clustering, in a data-driven, clinically independent, manner. Next, we established an in silico, subgroup signature-based, drug prediction pipeline. Investigated drugs included both those currently in practice and those who have been tested in SLE clinical trials and are listed in the iLINCS prediction databases. Finally, drug repurposing analysis was performed, to identify novel perturbagens that counteract group-specific SLE signatures. Results: Molecular taxonomy identified five distinct lupus molecular endotypes, each characterized by a unique gene module enrichment pattern. A group defined by strong neutrophilic signature encompassed almost exclusively patients with active nephritis, while a B-cell expression group included patients with severe lupus phenotype. Metabolic processes enrichment defined a group of patients with disease of moderate severity and serologic activity. Finally, patients with mild lupus features were distributed in two groups, which demonstrated enhanced basic cellular functions, myelopoiesis, and autophagy. The ability of different compounds to reverse the transcriptomic aberrancies observed in each patient group was examined. Bortezomib efficiently reversed disturbances in the “neutrophilic” cluster. Azathioprine and ixazomib might be a reasonable option for patients of the “B-cell” cluster, whereas fostamatinib appeared efficacious for the “Metabolism” patient subgroup. Conclusion: The clinical spectrum of SLE encompasses distinct molecular endotypes, each defined by unique pathophysiologic aberrancies, which can be utilized to guide personalized care and direct novel compound development. Acknowledgements: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390). Disclosure of Interests: None declared