Abstract
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.
Significance New ways to enhance PI efficacy are of major interest. We combine systems-level analyses to discover that PIs specifically interfere with splicing and that myeloma is selectively vulnerable to spliceosome inhibition. We reveal a new approach to advance myeloma therapy and uncover broader roles of splicing modulation in cancer.
Footnotes
Financial support: This work was supported by NIH/NCI P30CA083103 supporting UCSF Preclinical Therapeutic Core facility managed by B.C.H.), NIH/NHGRI T32HG008345 (to A.M.T.), the Damon Runyon Cancer Research Foundation Dale Frey Breakthrough Award (DFS 14-15), NIH/NCI K08CA184116, NIH/NIGMS DP2OD022552, and the UCSF Stephen and Nancy Grand Multiple Myeloma Translational Initiative (to A.P.W.) and NIH/NCI R01CA226851 (to A.N.B. and A.P.W.)
Declaration of Interests The authors declare no relevant conflicts of interest.
