Australian Researchers Unveil New Strategy to Combat Aggressive Cancers

Australian scientists have made significant strides in cancer research by unveiling a novel strategy to inhibit the growth of aggressive and hard-to-treat cancers through the targeting of a specialized molecular process known as 'minor splicing.' This groundbreaking discovery, published in the esteemed EMBO Reports on July 28, 2025, marks a potential turning point in the treatment of cancers that have long resisted conventional therapies.

The research, conducted by a team at the Walter and Eliza Hall Institute (WEHI) in Melbourne, demonstrates that blocking minor splicing can drastically reduce tumor growth in several types of cancer, particularly liver, lung, and stomach cancers. This approach is particularly promising for cancers driven by KRAS mutations, which are among the most common genetic alterations found in solid tumors.

"We are excited about our findings as they suggest a new method to tackle aggressive cancers that have limited treatment options," said Professor Joan Heath, head of the WEHI laboratory and a key author of the study. "Our strategy disrupts a fundamental process that these fast-growing cancers rely on, rather than targeting specific mutations that apply to only a subset of patients."

Minor splicing is a critical cellular process that involves the modification of long strands of RNA into shorter messenger RNA, which serve as templates for protein production. Although it constitutes only 0.05% of the splicing process, minor splicing affects approximately 700 of the 20,000 genes in the human genome. The research indicates that inhibiting minor splicing leads to the accumulation of DNA damage in cancer cells and activates a critical tumor suppressor pathway, ultimately resulting in cell death, while leaving healthy cells largely unharmed.

Dr. Karen Doggett, the first author of the study, emphasized the significance of their findings: "By reducing the activity of a protein encoded by the RNPC3 gene, a vital component of the minor splicing machinery, we managed to significantly slow tumor growth, which is particularly striking given the resilience of these cancers."

The research team utilized various models, including zebrafish, mouse models, and human lung cancer cells, to ensure the robustness of their findings. The study also uncovered that disrupting minor splicing activates the p53 tumor suppressor pathway, a crucial defense mechanism in the body’s response to cancer. This pathway is often mutated in many cancers, allowing for unchecked cell growth. "Blocking minor splicing can lead to DNA damage and activate this vital defense mechanism, suggesting that cancers with a functional p53 pathway would be especially vulnerable to our approach," Dr. Doggett added.

The study was supported by several prestigious organizations, including the National Health and Medical Research Council of Australia (NHMRC), the Ludwig Institute for Cancer Research, and the National Institute of Neurological Disorders and Stroke. To explore the development of compounds that could inhibit minor splicing, the research team collaborated with the National Drug Discovery Centre, screening over 270,000 drug-like molecules and identifying several promising candidates for further development.

Professor Heath concluded, "Our research validates minor splicing as a compelling therapeutic target. The challenge now is to develop a drug compound that can safely and effectively inhibit it. Given the breadth of cancer models and approaches used in our study, we are optimistic that our strategy could be relevant across various cancer types and not limited to a narrow set of conditions."

This innovative research not only highlights a new potential pathway for cancer treatment but also represents a collaborative effort across multiple disciplines and labs, showcasing the power of scientific collaboration in tackling complex medical challenges. As the scientific community continues to unravel the intricacies of cancer biology, this discovery offers renewed hope for patients battling aggressive cancers that currently have limited treatment options.