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

Enhancing the efficacy of proteasome inhibitors is a central goal in myeloma therapy. We proposed that signaling-level responses after PI would reveal new mechanisms of action that could be therapeutically exploited. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the m...

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Published inbioRxiv
Main Authors Hector Han-Li Huang, Ferguson, Ian D, Thornton, Alexis M, Lam, Christine Y T, Yu-Hsiu Tony Lin, Bastola, Prabhakar, Choudhry, Priya, Mariano, Margarette C, Marcoulis, Makeba D, Malato, Julia, Phojanakong, Paul, Martin, Thomas G, Wolf, Jeffrey L, Wong, Sandy W, Shah, Nina, Hann, Byron C, Brooks, Angela N, Wiita, Arun P
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 03.02.2019
Subjects
Gene expression
Interference
Multiple myeloma
Phosphorylation
Proteasome inhibitors
Ribonucleic acid
RNA
Splicing
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Summary:Enhancing the efficacy of proteasome inhibitors is a central goal in myeloma therapy. We proposed that signaling-level responses after PI would reveal new mechanisms of action that could be therapeutically exploited. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrated broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings led us to evaluate direct spliceosome inhibition in myeloma, which synergized with carfilzomib and showed potent anti-tumor activity. Functional genomics and exome sequencing further supported 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. Footnotes * "PI inducing IR in MM cells" section has been updated to clarify. Author list updated. Figure 3 revised, Figure 4 revised, Figure 5E revised, Figure 7D revised. Supplementary figures (S4A-B, S6C-D) and table S2 revised. Methods revised and distributed between main text methods and supplementary text methods.
DOI:10.1101/508549