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

Autor:	Huang HH; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Ferguson ID; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Thornton AM; Department of Biomolecular Engineering, University of California, Santa Cruz, CA, USA., Bastola P; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Lam C; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Lin YT; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Choudhry P; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Mariano MC; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Marcoulis MD; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Teo CF; Department of Physiology, University of California, San Francisco, CA, USA., Malato J; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Phojanakong PJ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Martin TG 3rd; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, CA, USA., Wolf JL; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, CA, USA., Wong SW; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, CA, USA., Shah N; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, CA, USA., Hann B; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Brooks AN; Department of Biomolecular Engineering, University of California, Santa Cruz, CA, USA., Wiita AP; Department of Laboratory Medicine, University of California, San Francisco, CA, USA. Arun.wiita@ucsf.edu.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Arun.wiita@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Apr 22; Vol. 11 (1), pp. 1931. Date of Electronic Publication: 2020 Apr 22.
DOI:	10.1038/s41467-020-15521-4
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu