Blocking Minor Splicing: A Promising Approach to Hindering Tumor Growth Across Multiple Cancer Types

Researchers from the Walter and Eliza Hall Institute have uncovered an innovative strategy to combat aggressive and difficult-to-treat cancers by targeting the process known as minor splicing. Published in EMBO Reports, their study titled "Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers" reveals that inhibiting minor splicing significantly slows tumor progression in liver, lung, and stomach cancers while sparing healthy cells.

Minor splicing is a molecular process responsible for correctly editing RNA transcripts, affecting roughly 0.05% of genes—around 700 of the 20,000 genes in the human genome. Despite its small scope, this process is vital for the expression of genes that control cell growth and division. The research demonstrated that blocking this process leads to DNA damage specifically in cancer cells, activating the p53 tumor suppressor pathway and inducing cell death. Remarkably, healthy cells are largely unaffected by this inhibition.

The study utilized animal models, human cells, and zebrafish to validate its findings. Reducing activity of a protein encoded by the RNPC3 gene—key to the minor splicing machinery—resulted in a notable decrease in tumor size. This disruption also triggered the p53 pathway, an essential defense mechanism often compromised in cancer, highlighting the potential for this approach to be especially effective in tumors with functional p53.

Furthermore, the research identified potential drug candidates through a screening of over 270,000 molecules at the National Drug Discovery Center. The goal is to develop safe and effective inhibitors of minor splicing. This approach offers a broad, mutation-independent strategy to target many cancers, particularly those driven by common mutations like KRAS, which have historically been hard to treat.

Professor Joan Heath emphasized the novelty of disrupting a fundamental cellular process rather than targeting specific mutations, paving the way for more inclusive cancer treatments. By impairing minor splicing, this strategy exploits a fundamental vulnerability in cancer cells, potentially leading to therapies that are both potent and less toxic.

The findings open avenues for developing new treatments that could benefit patients with limited options, especially for aggressive tumors resistant to conventional therapies. The research underscores that targeting fundamental cellular mechanisms like minor splicing could transform the landscape of cancer therapy, offering hope for more effective and less harmful options in the future.