A protein in tumour cells could be targeted to treat some types of aggressive cancer including those of the brain, blood, skin, and kidney, scientists have reported.
A team from the Wellcome Sanger Institute, University of Cambridge and Harvard University have identified METTL1, an RNA-modifying protein that plays a key role in transforming normal tissue into cancer.
They say inhibiting it effectively destroys cancer cells in laboratory models, including in cell lines and mice, while leaving healthy cells unharmed.
The research, published in the latest edition of Molecular Cell, concludes that there is sufficient evidence for developing drugs to block METTL1, which would provide new treatment options for people with aggressive brain, blood, skin, and kidney cancers.
RNA-modifying proteins, in particular the METTL family, are involved heavily in cell replication and have been found in higher levels in some cancer cells. They are also associated with poorer outcomes.
In a previous study, Dr Konstantinos Tzelepis, his team at the University of Cambridge and colleagues at the Wellcome Sanger Institute, used CRISPR-Cas9 gene-editing technology to screen cancer cells for vulnerable points and identified the METTL1 gene as a target for drug development.
Building on these findings, this new research found that mutations in the METTL1 gene lead to higher levels of the METTL1 protein and cause the cells to replicate faster and transform into a cancerous state, producing highly aggressive tumours.
However, when they inhibited the METTL1 protein by knocking out the gene in both laboratory and mice models, cancer cell growth stopped and normal healthy cells were unharmed.
Co-lead author and group leader Dr Tzelepis said: “This study provides another great example of what is possible with the use of CRISPR technologies and how we can take and prioritise precise genetic information and turn it into something of potential clinical benefit.
“Targeting RNA-modifying proteins can effectively destroy cancer cells and we hope that this research will provide the evidence necessary for drugs to be developed that target METTL1, potentially providing a new therapy against aggressive cancers with clear and unmet therapeutic need.”
Co-lead author Professor Richard Gregory, from Boston Children’s Hospital and Harvard Medical School, Boston, added: “Cancer cells benefit from an unregulated cell cycle, leading to increased replication, and while some of the reasons behind this are known, there is still a lot to discover.
“This research illuminates deeply the role of the METTL1 protein in cancer development and proves that mutations in this gene can cause a cell to become cancerous. The more we understand about the genetic basis of cancer and how we can combat this, the more life changing targeted treatments we can create.”
First author Dr Esteban Orellana, research fellow at Boston Children’s Hospital, said the findings show that targeting METTL1 is an effective treatment against certain cancers.
“This is important as it could mean that there will be fewer unpleasant side effects of a potential new treatment. The next step for this research is to try and develop a small molecule inhibitor to block METTL1 to see if our encouraging results can be translated across to the clinic,” he added.
The team has also developed a small-molecule inhibitor for METTL3 to help treat acute myeloid leukaemia, which will enter clinical trials in 2022.
METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Molecular Cell 4 August 2021
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