Synthetic lethality of p97 inhibition and PSMC2-overexpressionovercomes bortezomib resistance in multiple myeloma

Higher PSMC2 messenger RNA in multiple myeloma cells is linked to inferior progression-free and overall survival after bortezomib monotherapy, identifying a resistance-associated vulnerability.

• Why it matters: Transcriptomic heterogeneity in multiple myeloma is linked to variable outcomes, but actionable targets explaining bortezomib resistance and prognosis are not well defined.
• What they did: Genomic profiling of patient tumors identified PSMC2 as a classifier; CB-5339, a p97/VCP inhibitor, was tested in MM cells engineered to overexpress or knock out PSMC2, including proteasome activity and ubiquitin-chain assays.
• The result: CB-5339 was synthetic lethal in PSMC2-overexpressing MM cells, and co-treatment with bortezomib synergistically reduced growth of PSMC2-overexpressing myeloma xenografts in mice.

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