Background/Purpose: Systemic lupus erythematosus (SLE) therapies elicit distinct transcriptional responses, yet a subset of patients fails to achieve clinical remission. To guide precision repurposing, we applied a transcriptome-driven strategy to identify compounds that either mimic the molecular effects of standard therapies or reverse gene expression profiles associated with treatment resistance.

Methods: Paired whole-blood transcriptomes from 31 SLE patients treated with rituximab (n=8), belimumab (n=13), or cyclophosphamide (n=10) were analyzed to define drug-specific signatures (absolute log₂FC > 0.58, p < 0.05). A “refractory SLE” signature was derived by comparing gene expression at 6 months between responders and non-responders. Signatures were queried against L1000CDS² and CMAP2 databases to identify compounds that replicate or reverse these transcriptional patterns. Drug-gene interactions were explored using the DGIdb database.

Results: Transcriptional mimics of standard therapies were largely drug-specific, reflecting distinct modes of action. Rituximab’s signature aligned with mTOR blockers (everolimus, dactolisib), PI3K inhibitors (PIK-75, ZSTK474), JAK2 inhibitors (fedratinib) and agents downregulating the p38-MAPK pathway (OXA). Belimumab’s mimics included BCL-2 and ERK inhibitors (FR180204). Cyclophosphamide’s replicants entailed JNK and NETosis-targeting agents. For refractory SLE, inverse transcriptional alignment was accomplished by several mechanistically diverse compounds including HSP90 inhibitors (geldanamycin, tanespimycin), tyrosine kinase inhibitors (dasatinib, lapatinib), and ferroptosis inducers (CX-5461) Notably, proteasome inhibitors (bortezomib, carfilzomib, ixazomib) emerged as promising agents based on gene interaction mapping, implicating plasma cells in treatment-resistant disease course.

Conclusion: Our analysis delineates molecular correlates of therapeutic response and identifies candidate drugs capable of emulating molecular effects of standard SLE therapies or reversing gene expression patterns associated with treatment failure, offering a framework for drug repurposing in difficult-to-treat SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-treatment-resistant-systemic-lupus-erythematosus-through-transcriptome-informed-drug-repurposing/