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

Hector H. Huang, Ian D. Ferguson, Alexis M. Thornton, Prabhakar Bastola, Christine Lam, Yu-Hsiu T. Lin, Priya Choudhry, Margarette C. Mariano, Makeba D. Marcoulis, Chin Fen Teo, Julia Malato, Paul J. Phojanakong, Thomas G. Martin, Jeffrey L. Wolf, Sandy W. Wong, Nina Shah, Byron Hann, Angela N. Brooks and Arun P. Wiita ()
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Hector H. Huang: University of California
Ian D. Ferguson: University of California
Alexis M. Thornton: University of California
Prabhakar Bastola: University of California
Christine Lam: University of California
Yu-Hsiu T. Lin: University of California
Priya Choudhry: University of California
Margarette C. Mariano: University of California
Makeba D. Marcoulis: University of California
Chin Fen Teo: University of California
Julia Malato: University of California
Paul J. Phojanakong: University of California
Thomas G. Martin: University of California
Jeffrey L. Wolf: University of California
Sandy W. Wong: University of California
Nina Shah: University of California
Byron Hann: University of California
Angela N. Brooks: University of California
Arun P. Wiita: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15521-4

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