Synthetic lethality of p97 inhibition and PSMC2-overexpressionovercomes bortezomib resistance in multiple myeloma
The aim of the present study was to analyze genomic profiles obtained from multiple myeloma (MM) patient tumors to identify prognostic classifiers of clinical response and survival following bortezomib monotherapy and then target key actionable classifiers that underly bortezomib resistance. We discovered higher levels of proteasome PSMC2 messenger RNA in myeloma cells from patients that did not…
Researchers investigated genomic profiles of multiple myeloma (MM) tumors to uncover molecular markers of clinical response and survival following bortezomib treatment. They observed elevated levels of PSMC2 messenger RNA in non-responsive myeloma cells and noticed a negative association between PSMC2 expression and progression-free or overall survival.
Through pharmacological screening, they found that CB-5339, an ATP-competitive inhibitor of p97/VCP, showed synthetic lethality in MM cells overexpressing PSMC2. Co-immunoprecipitation of 26S proteasomes from PSMC2-overexpressing cells exhibited enhanced activity and lower bortezomib sensitivity compared to cells with PSMC2 knockout.
The presence of K48- and K63-linkage-specific ubiquitin chains on 26S proteasomes was more abundant in PSMC2-KO cells after bortezomib treatment. Western blotting revealed increased levels of 19S RPs, 26S proteasomes, and PSMC2-PSMC1-PSMD2 subcomplex in PSMC2-overexpressing cells. When CB-5339 and bortezomib were co-administered, they exhibited synergistic effects on tumor cells from bortezomib-exposed MM patients and reduced growth of PSMC2-overexpressing myeloma xenografts in mice.
The study highlights a genetic weakness behind proteasome-intrinsic bortezomib resistance and validates synthetic lethality as a strategy for therapeutic intervention, emphasizing the role of transcriptomic heterogeneity in MM.
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