New Australian Research Targets Minor Splicing to Combat Cancer

In a groundbreaking study, researchers from the Walter and Eliza Hall Institute (WEHI) in Australia have identified a novel therapeutic approach to target aggressive cancers by inhibiting a cellular process known as minor splicing. Published in the journal EMBO Reports on July 30, 2025, the research reveals that blocking this essential mechanism, which affects only 0.05% of gene expression, can significantly hinder the growth of tumors driven by KRAS mutations—one of the most common and challenging targets in cancer treatment.

Minor splicing is a critical aspect of RNA processing that allows cells to generate messenger RNA (mRNA) necessary for protein production. While major splicing accounts for 99.5% of this function, minor splicing has been largely overlooked until now. According to Professor Joan Heath, head of the laboratory at WEHI and a leading author of the study, "The KRAS mutations come in various forms, making them incredibly difficult to treat. Our approach disrupts a fundamental process that these fast-growing cancers depend on, offering a potential treatment avenue for a wider range of patients."

The significance of this discovery lies in its ability to activate the body’s inherent cancer-defense mechanisms. By inhibiting minor splicing, the research team observed an accumulation of DNA damage in cancer cells, triggering the activation of the p53 tumor suppressor pathway, which is crucial for regulating cell growth and death. Dr. Karen Doggett, the first author of the study, emphasized the striking results achieved through reducing the activity of the RNPC3 protein, stating, "Halving the amount of this protein significantly reduced tumor burden, which is especially notable given the resilience of these cancers."

This research is particularly impactful for liver, lung, and stomach cancers, which often feature KRAS mutations. The findings suggest that cancers retaining a functional p53 pathway may be especially susceptible to this treatment strategy. The WEHI-led study utilized various models, including zebrafish and mouse models, to validate the results across multiple tumor types, adding robustness to their findings.

Moreover, the research team is collaborating with the National Drug Discovery Centre at WEHI to screen over 270,000 drug-like molecules for potential compounds that can effectively inhibit minor splicing. Professor Heath noted, "We have established minor splicing as a compelling therapeutic target, and our next challenge is to develop a drug compound that can safely and effectively inhibit it."

This study not only represents a significant advancement in cancer research but also highlights the potential for developing therapies that are both more effective and less toxic than conventional treatments. Supported by the National Health and Medical Research Council of Australia and the Ludwig Institute for Cancer Research, the research underscores the value of interdisciplinary collaboration in addressing complex health challenges.

As the global cancer community continues to search for innovative treatments, the findings from WEHI may pave the way for new, less invasive options for patients facing aggressive cancers that currently have limited therapeutic alternatives. This research marks a hopeful milestone in the ongoing battle against cancer, demonstrating that even the smallest cellular processes can yield significant impacts on treatment outcomes.