Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer
Verena Wagner1,2,3,4, Laura Bousset5,6, Mariana Ascensão-Ferreira7,8
1MRC Laboratory of Medical Sciences (LMS), London, UK. v.wagner@med.uni-tuebingen.de.
Abstract:
RAS family proteins, including HRAS, NRAS, and KRAS, are frequently mutated in cancer. Although there has been recent success in designing inhibitors that target oncogenic RAS, they elicit resistance and treating RAS-driven cancer remains difficult. Here, employing a proteomic analysis, we find that multiple spliceosome components are upregulated in the nuclei of cells undergoing RAS-induced senescence. This upregulation depends on RAS signalling and occurs in both senescent preneoplastic and fully transformed cancer cells. Spliceosome components are also highly expressed in preneoplastic and cancerous lesions in human and murine lung, liver, colorectal, and pancreatic cancers. Using siRNA screens, we identify six spliceosome components, including SF3B1 and RBM39, that are essential in cells expressing oncogenic RAS. We find that SF3B1 is required in these cells for maintaining splicing fidelity. By combining transcriptome and splicing analyses with functional screens, we identify the RNA Pol II-associated factor SPT5 as a key mediator of the SF3B1 effects. Importantly, using mouse models of liver cancer, we show that RBM39 and SF3B1 inhibitors are effective in targeting both preneoplastic lesions and aggressive tumours expressing oncogenic RAS. In summary, our study highlights the spliceosome as a promising target for RAS-driven cancers capable of inhibiting both cancer initiation and progression.
Insights
Targeting the spliceosome, essential for RAS-driven cancers, offers a new therapeutic strategy. Inhibitors targeting SF3B1 and RBM39 show promise in treating both preneoplastic lesions and aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RAS family proteins (HRAS, NRAS, KRAS) are frequently mutated in various cancers.
- While oncogenic RAS inhibitors exist, acquired resistance makes treating RAS-driven cancers challenging.
Purpose of the Study:
- To investigate the role of the spliceosome in RAS-driven cancers.
- To identify novel therapeutic targets within the spliceosome for RAS-driven malignancies.
Main Methods:
- Proteomic analysis to identify upregulated nuclear spliceosome components in RAS-induced senescence.
- siRNA screens to determine essential spliceosome components in oncogenic RAS-expressing cells.
- Transcriptome and splicing analyses combined with functional screens to identify key mediators.
Main Results:
- Spliceosome components are upregulated in RAS-signaling dependent senescence and highly expressed in human and murine preneoplastic and cancerous lesions.
- SF3B1 and RBM39 were identified as essential spliceosome components for oncogenic RAS-driven cells, with SF3B1 crucial for splicing fidelity.
- SPT5 was identified as a key mediator of SF3B1's effects.
- Inhibitors targeting RBM39 and SF3B1 demonstrated efficacy in mouse models of liver cancer, targeting both preneoplastic and aggressive tumors.
Conclusions:
- The spliceosome is a promising therapeutic target for RAS-driven cancers.
- Targeting specific spliceosome components like SF3B1 and RBM39 can inhibit both cancer initiation and progression.
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