Abstract
Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in 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.
Highlights
Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy
We instead consider the indirect effects on phosphorylation induced by PI exposure
We investigated the hypothesis that the intron retention (IR) phenotype we observed after Cfz could be related to PI-induced heat shock
Summary
Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. 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. We and others[9,12,13] have proposed targeting mediators of the heat shock response as potential combination therapies with PIs. one unresolved question is whether proteasome inhibition may carry additional effects on plasma cells that are not revealed by mRNA or protein abundance analysis alone. We propose the spliceosome as a new and potentially selective therapeutic target in myeloma
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