Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.

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.