EMBO Reports<\/a>, shows that blocking minor splicing can markedly slow tumour growth in liver, lung and stomach cancers, while leaving healthy cells largely unharmed. The research in animal models and human cells demonstrates the potential of this strategy to target cancers driven by mutations in common cancer-causing genes.<\/p>\nSplicing is how cells turn long strands of RNA into shorter pieces called messenger RNA, which provide the template for the production of proteins. While major splicing carries out 99.5% of this work, minor splicing is an indispensable process for the remaining 0.5% of genes, affecting about 700 of the 20,000 genes in the human genome.<\/p>\n
Although it affects only a small subset of genes, minor splicing is crucial for the correct expression of genes that drive cell growth and division \u2014 making it a potential Achilles heel for cancer cells. Importantly, many of these genes are commonly hijacked by cancers driven by KRAS mutations, which are among the most frequent genetic changes found in solid tumours.<\/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 effort there has been only limited progress so far,\u201d 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 said to be the first to demonstrate the impact of inhibiting minor splicing in in vivo models of solid tumours. The study found that reducing the activity of a protein encoded by the RNPC3 gene \u2014 an essential component of the minor splicing machinery \u2014 caused the accumulation of DNA damage in cancer cells, significantly slowing tumour growth in liver, lung and stomach cancers.<\/p>\n
\u201cJust by halving the amount of this protein, we were able to significantly reduce tumour 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 tumour suppressor pathway, a critical defence mechanism in the body\u2019s fight against cancer. The p53 protein responds to DNA damage by stalling cell division, initiating DNA repair or triggering cell death \u2014 but this 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 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
According to Heath, one of the strengths of the study is the breadth of models and tumour types used.<\/p>\n
\u201cWe didn\u2019t just test one kind of cancer or use one analysis method,\u201d she said. \u201cThis 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
To search for compounds that might inhibit minor splicing, the research team has turned to the WEHI-headquartered National Drug Discovery Centre<\/a>, 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 \u2014 now the challenge is to develop a drug compound that can safely and effectively inhibit it,\u201d Heath concluded.<\/p>\n
Image caption:\u00a0A section of liver tumour in a zebrafish shows liver cell DNA (cyan), cancer cells with KRAS activity (purple), and DNA damage (white). The study found that lowering a key protein involved in minor splicing causes DNA damage selectively in cancer cells, leading to the expression of the p53 tumour suppressor protein. <\/p>\n","protected":false},"excerpt":{"rendered":"New research led by the Walter and Eliza Hall Institute (WEHI) has revealed a promising new strategy to…\n","protected":false},"author":2,"featured_media":337315,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3846],"tags":[1204,120555,267,120554,70,16,15,120552,120553],"class_list":{"0":"post-337314","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-cancer","9":"tag-embo-reports","10":"tag-genetics","11":"tag-minor-splicing","12":"tag-science","13":"tag-uk","14":"tag-united-kingdom","15":"tag-walter-and-eliza-hall-institute","16":"tag-wehi"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/115013466557638623","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/337314","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=337314"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/337314\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/337315"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=337314"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=337314"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=337314"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
![\"Genetic](\"https:\/\/d1v1e13ebw3o15.cloudfront.net\/data\/89725\/pool_and_spa_master\/..jpg\" "\\"Genetic")
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