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

Hector H Huang1, Ian D Ferguson1, Alexis M Thornton2

  • 1Department of Laboratory Medicine, University of California, San Francisco, CA, USA.

Nature Communications
|April 24, 2020
PubMed

Insights

Proteasome inhibitors (PI) in myeloma therapy can be enhanced by targeting the spliceosome. This study reveals spliceosome interference as a novel PI mechanism, offering a new therapeutic strategy for myeloma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Enhancing proteasome inhibitor (PI) efficacy is crucial for effective multiple myeloma therapy.
  • Investigating signaling pathways post-PI treatment may uncover novel therapeutic targets.
  • Carfilzomib, a proteasome inhibitor, is a key treatment for myeloma.

Purpose of the Study:

  • To explore signaling-level responses to proteasome inhibitors to identify new therapeutic strategies in myeloma.
  • To investigate the role of the spliceosome in myeloma therapy and its interaction with proteasome inhibitors.
  • To evaluate direct spliceosome inhibition as a therapeutic approach in myeloma.

Main Methods:

  • Unbiased phosphoproteomics to analyze protein phosphorylation changes after carfilzomib treatment.
  • Transcriptome analysis to identify alterations in RNA splicing, including intron retention and alternative splicing.
  • Functional genomics and exome sequencing to validate the spliceosome as a therapeutic target in myeloma.
  • In vitro and in vivo studies to assess the synergistic effects of spliceosome inhibitors and carfilzomib.

Main Results:

  • Phosphoproteomics revealed significant phosphorylation changes in splicing-related proteins following carfilzomib treatment.
  • Transcriptome analysis showed widespread intron retention and altered splicing of key cellular machinery components.
  • Direct spliceosome inhibition demonstrated synergistic effects with carfilzomib, exhibiting potent anti-tumor activity in myeloma models.
  • Genetic analyses confirmed the spliceosome as a specific vulnerability in myeloma.

Conclusions:

  • Splicing interference represents an unrecognized mechanism of action for proteasome inhibitors in myeloma.
  • The spliceosome is a critical regulator of cellular processes affected by proteasome inhibition.
  • Targeting the spliceosome, in combination with proteasome inhibitors, presents a promising therapeutic strategy for multiple myeloma.

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