Researchers at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London have identified an overworked cog in the cellular machinery of tumour cells that could be targeted by new treatment options for an aggressive class of cancers. The team found that blocking this system with known drugs selectively killed these cancers – those linked to mutations in a set of genes known as RAS – and caused mouse tumours to shrink, suggesting a new strategy for tackling cancers that often resist treatment.
Almost a third of all cancers, including some of the hardest to treat, contain mutations in RAS genes. This set of oncogenes (genes that, when mutated, can cause cancer) act as a molecular switch controlling cell proliferation. When the switch malfunctions, treatment-resistant cancers with poor prognosis are often the result. Although new drugs that directly target specific RAS mutations have recently emerged, treatment options remain limited, and resistance frequently develops.
Unrestrained cell division in tumours puts pressure on each cell, as they work at an accelerated pace to proliferate. Much of this activity must be processed through the cell’s editing room: the spliceosome. It’s where RNA – strands of genetic material copied from the original DNA blueprint – is refined to its final version, removing unwanted sections before it can be used as the template to produce the many proteins needed for all healthy cellular activity. New research, published today in Nature Communications and led by Dr Verena Wagner, formerly a postdoctoral researcher at the LMS and now at University Hospital Tübingen, Germany and Dr Laura Bousset, a postdoctoral researcher at the LMS, has found that in RAS cancers this editing room is overloaded, making it a weak spot. By targeting the spliceosome, stopping it from working, they may have discovered a new way to treat some of our most aggressive cancers.
Finding the vulnerability
Cancer-driving mutations like RAS push some cells into a stressed state known as senescence. Senescent cells do not divide, but although they don’t proliferate themselves, they secrete signals that wreak havoc around them, causing inflammation and disrupting tissue homeostasis. It is this state that the Senescence research group at LMS were focussed on. “We are interested in oncogene-induced senescence,” Laura said. “That’s a particular state of senescence when cells are stressed, in response to cancerous signals. Our idea is to try to eliminate these cells that could give rise to cancers. We look for their vulnerabilities, and that’s how we ended up looking at components of the spliceosome, called splicing factors.”
In cells driven to a senescent state by oncogenic RAS mutations they discovered a striking reliance on certain splicing factors. Laura continued, “this represented a new vulnerability of these senescent cells, which had not been described before. We identified two splicing factors in particular, SF3B1 and RBM39, for which drugs already exist.”
Blocking RNA processing to kill RAS cells
With these splicing factors identified as being overactive in Ras-expressing cells, the question was whether eliminating them would take down RAS-expressing cells. “We showed that by targeting these factors we could kill senescent cells expressing RAS and, more importantly, RAS-expressing cells in different cancer models – liver cancer, colorectal cancer and pancreatic cancer,” said Laura. “Overall, we show that splicing is a previously unrecognised Achilles’ heel of RAS-driven cancers and that targeting this process could open new therapeutic opportunities.”
Clinical impact, further research
This study has identified that drugs already familiar to researchers have huge potential for some of the most treatment-resistant, deadly cancers.
“RAS-driven cancers are difficult to treat. Only a few inhibitors are clinically available. We aim to identify further vulnerabilities. Our lab focuses on biology, not drug development, but collaborations may help translate these findings,” says Professor Jesús Gil, senior author and Head of the Senescence group at the LMS.
The research showed that the inhibitors RBM39 and SF3B1 are effective in targeting both pre-cancerous cell clusters and aggressive RAS-driven tumours, suggesting this treatment could do two things: prevent cancer from emerging and slow the progression of existing tumours.
The potential impact is broad, potentially having implications for other types of cancer and different conditions altogether. Jesús explains, “In recent years many papers have described spliceosome activation in cancer, it is not unique to RAS. For example, cancers driven by other mutations also show spliceosome upregulation. What is important here is that for RAS cancers, which can be so harmful, the spliceosome activity creates a specific vulnerability we can exploit. It gives us a new way to attack and treat senescent cells, and cancer itself, that we haven't previously had."
These breakthroughs have uncovered a new approach to targeting RAS-expressing cells and suggest that dismantling the support systems tumours rely on could provide a new window of opportunity for treating cancers in the future.
This work was an international collaboration between teams at the LMS, Imperial, The University of Lisbon in Portugal and University Hospital Tübingen in Germany amongst others.
The study was funded by the Medical Research Council and a programme grant from Cancer Research UK.
Nature Communications
Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer
15-Apr-2026