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

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.

LMNB2 is a prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

“…It provides a critical molecular mechanism, which changes in diverse cancer types. [18][19][20] However, further studies are required to investigate the biological functions of LMNB2. The kinases-target gene set enrichment analysis of the LMNB2 network system revealed that kinase gene sets (kinase_CDK1, kinase_PLK1, kinase_CDK2, kinase_ATM, and kinase_AURKB) were significantly correlated with LMNB2.…”

“…The mRNA splicing involves the removal of introns and exons and the formation of mature mRNA. It provides a critical molecular mechanism, which changes in diverse cancer types 18–20 . However, further studies are required to investigate the biological functions of LMNB2.…”

Alternative splicing and cancer: a systematic review

“…A recent study on multiple myeloma, using unbiased phosphoproteomics and transcriptomic/exomic sequencing following treatment with the proteasome inhibitor carfilzomib, found that the splicing-related proteins underwent the most prominent phosphorylation changes, and that the spliceosome might be a specific vulnerability in this hematological malignancy. 185 Kahles et al 186 have provided a landscape of the splicing differences between the most common tumors and the healthy counterpart samples from 8,705 patients, suggesting that the increased splicing diversity in tumors might be an effect rather than a cause of oncogenesis. They also highlighted that certain cancer-specific alternative splice isoforms could produce neo-antigens, which can be used as a novel strategy for cancer immunotherapy (see next section).…”

Transcriptomic Analysis Revealed an Emerging Role of Alternative Splicing in Embryonal Tumor with Multilayered Rosettes

“…Cancer cells are capable of dynamically changing gene expression and favoring the expression of aberrant oncogenic splice variants to overcome stresses within the tumor microenvironment [ 38 ]. Abnormal AS is now regarded as a valuable indicator of carcinogenic processes and prognosis, as well as a potential target of treatment in several types of cancer [ 39 , 40 , 41 , 42 , 43 , 44 ].Not only is it a valuable diagnostic marker of ETMRs [ 45 ], LIN28A overexpression can be functionally significant as well. LIN28A was reported as a regulator of self-renewal capacity in cancer stem cells, cellular metabolism, and the cell cycle through binding and repression of let-7 microRNAs [ 12 , 46 , 47 ].…”