Synthetic lethal targeting of PSMC2-dependent p97-adapted proteasome complexes that confer chemoresistance in multiple myeloma

作者：James J. Driscoll, James J. Ignatz-Hoover, Ehsan Malek, John D'Cruz, Wei Huang, Derek J. Taylor · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-2176 · 被引用次数：1 · 研究领域：Ubiquitin and proteasome pathways、Cell death mechanisms and regulation、Protein Degradation and Inhibitors

Abstract Introduction. Multiple myeloma (MM) is the second most common hematological malignancy. The emergence of novel agents has significantly extended patient survival, however, those with certain cytogenetic and clinical features are at risk of poor outcome. While proteasome inhibitors (PIs), e.g., bortezomib (Btz), have transformed MM care, many patients do not respond to therapy, and drug resistance inevitably emerges through molecular mechanisms that remain incompletely characterized. Here, we hypothesized that the expression of proteasome genes in patient tumor cells could inform responses to Btz and identify novel, actionable therapeutic targets to improve patient outcome. Methods. Thephase III APEX trial randomized MM patients that had consented to genomic analyses of tumor samples obtained prior to treatment to receive either Btz or high-dose dexamethasone (Dex). We compared the expression of proteasome genes in Btz responders (Btz-Rs) to non-responders (Btz-NRs) and identified 13 genes significantly overexpressed in Btz-NRs. To corroborate the APEX study results, we analyzed the CoMMpass dataset; a longitudinal study that collects tissue, genetic information, and clinical outcomes from >1,100 NDMM patients. To identify drugs that specifically targeted PSMC2-overexpressing cells, a high throughout screen (HTS) was performed using drugs that targeted ER-dependent protein degradation. Drugs that selectively induced synthetic lethality in PSMC2-overexpressing w...