Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM).  We proposed that signaling-level responses after PI would reveal new means to enhance efficacy.  Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components.  Spliceosome modulation was invisible to RNA or protein abundance alone.  Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference.  Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity.  Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma.  Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma. SOURCE: Hector,Han-Li,HuangWiita Lab University of California San Francisco

Pluto Bioinformatics

GSE124510: Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma