In a major breakthrough published in EMBO Reports, researchers found that blocking this tiny RNA process can dramatically reduce tumor growth in liver, lung, and stomach cancers. Even more promising, healthy cells are mostly unaffected.<\/p>\n
The study, led by the WEHI medical research institute, used both animal models and human cancer cells to show that this strategy is especially effective against tumors driven by common cancer-causing mutations. The findings open a new path toward treatments that are more precise and potentially less harmful than conventional therapies.<\/p>\n
Cells rely on a process called splicing to transform long strands of RNA into messenger RNA, the form needed to build proteins.<\/p>\n
Most of this work, about 99.5 percent, is handled by what\u2019s known as major splicing. But the remaining 0.05 percent of genes depend on a second, much smaller system called minor splicing. Although this process only affects around 700 of the 20,000 human genes, its role is essential.<\/p>\n
New research has found that when minor splicing is blocked, DNA damage builds up in cancer cells, triggering a natural tumor-suppressing response that leads those cells to die. What\u2019s especially promising is that healthy cells appear to be largely unaffected by this disruption.<\/p>\n
Even though minor splicing influences only a small portion of genes, it plays a vital role in regulating those that control how cells grow and divide. This makes it a promising target for stopping cancer.<\/p>\n
Many of the genes controlled by minor splicing are hijacked by cancers driven by KRAS mutations, which are among the most common genetic changes in solid tumors.<\/p>\n
WEHI laboratory head Professor Joan Heath said scientists have long known that KRAS is central to many aggressive cancers, but have struggled to turn that knowledge into broadly effective treatments.<\/p>\n
\u201cKRAS mutations come in a variety of flavours, making them extremely hard to treat, so even with decades of scientific effor,t there has been only limited progress so far,\u201d Prof Heath said.<\/p>\n
\u201cBut our approach is different. Instead of trying to target specific mutations that may only apply to a subset of patients, we\u2019re disrupting a fundamental process that these fast-growing cancers rely on.<\/p>\n
\u201cThis research offers a new way to tackle a problem that\u2019s long resisted conventional approaches, with the potential to help a much wider group of patients.\u201d<\/p>\n
Using zebrafish and mouse models, as well as human lung cancer cells, the WEHI-led research is the first to demonstrate the impact of inhibiting minor splicing in in vivo models of solid tumors.<\/p>\n
The study found reducing the activity of a protein encoded by the RNPC3 gene \u2013 an essential component of the minor splicing machinery \u2013 significantly slows tumor growth in liver, lung and stomach cancers.<\/p>\n
\u201cJust by halving the amount of this protein, we were able to significantly reduce tumor burden,\u201d said Dr. Karen Doggett, first author of the study.<\/p>\n
\u201cThat\u2019s a striking result, especially given how resilient these cancers usually are.\u201d<\/p>\n
The study also revealed that disrupting minor splicing triggers the p53 tumor suppressor pathway, a critical defence mechanism in the body\u2019s fight against cancer.<\/p>\n
Dubbed the \u2018guardian of the genome\u2019, the p53 protein responds to DNA damage by stalling cell division, initiating DNA repair or triggering cell death. This well-known pathway is frequently mutated or disabled in many cancers, allowing these cells to grow unchecked.<\/p>\n
\u201cBlocking minor splicing leads to DNA damage and activates this critical defensive response, which means cancers with a functional p53 pathway are likely to be especially vulnerable to this strategy,\u201d Dr. Doggett said.<\/p>\n
\u201cThis opens the door to treatments that could be both more effective and less toxic, offering hope for patients with aggressive cancers that currently have limited options.\u201d<\/p>\n
To search for compounds that might inhibit minor splicing, the research team turned to the National Drug Discovery Centre headquartered at WEHI, with a screen of over 270,000 drug-like molecules identifying several promising hits.<\/p>\n
\u201cWe\u2019ve validated minor splicing as a compelling therapeutic target \u2013 now the challenge is to develop a drug compound that can safely and effectively inhibit it,\u201d Prof Heath said.<\/p>\n
The research draws on WEHI\u2019s deep expertise in gene discovery and cancer biology, showcasing the power of collaboration across multiple labs and technologies.<\/p>\n
\u201cOne of the strengths of this study is the breadth of models and tumor types we used,\u201d Prof Heath said.<\/p>\n
\u201cWe didn\u2019t just test one kind of cancer or use one analysis method. This diversity in our approach gives us confidence that our strategy could be relevant across many forms of cancer, and not just in a narrow set of conditions.\u201d<\/p>\n
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