RNA-modifying protein offers a possible lead for treating aggressive cancers

A protein that modifies RNAs, called METTL1, could be a target for treating some aggressive, difficult-to-treat cancers, suggests new research in Molecular Cell. The study provides evidence that blocking METTL1 curbs cancer cells’ ability to grow, selectively killing them, and the researchers believe it could be targeted with drugs.

METTL1 and related proteins had previously been found in higher levels in certain cancer cells, including some brain, blood, pancreatic, and skin cancers. Examining data from The Cancer Genome Atlas, the new study confirms that expression of the METTL1 gene is amplified in various cancers, including glioblastoma and sarcoma, and is associated with poor survival. It also demonstrates that the copy number amplification of the METTL1 gene leads to excessive amounts of METTL1 protein. This, in turn, causes previously normal cells to replicate faster and transform into a malignant state, producing highly aggressive tumors. 

“This research illuminates deeply the role of the METTL1 protein in cancer development and proves that its over-production can cause a cell to become cancerous,” says Richard Gregory, PhD, of the Stem Cell Research Program at Boston Children’s Hospital and the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Gregory co-led the study with Konstantinos Tzelepis, PhD, of the University of Cambridge in collaboration with the Wellcome Sanger Institute.

Blocking malignant transformation

METTL1 is one of a family of RNA-modifying proteins involved in cell replication. The RNA modification increases translation and production of growth-promoting, oncogenic proteins, the researchers showed.

When they inhibited production of METTL1 genetically — using a short hairpin RNA to knock down the METTL1 gene or CRISPR editing to delete it — they stopped cancer cell growth in laboratory and mouse models while leaving non-cancerous cells unharmed. When they did the opposite — over-expressing the METTL1 gene — they saw increased cell proliferation, accelerated cell cycle progression, enhanced colony formation, and, in mice, increased tumor formation.

“Cancer cells benefit from an unregulated cell cycle, leading to increased replication,” says Gregory. “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.”

A druggable target?

The researchers now hope to develop a small-molecule drug that would block METTL1, without the need for genetic manipulation. A small-molecule inhibitor for a similar protein, METTL3, has been developed to help treat acute myeloid leukemia, and is expected to enter clinical trials in 2022. If a similar drug could be developed to target METTL1, it could potentially be used to treat a wide range of aggressive cancers with high levels of METTL1 protein.

“Our research gives strong evidence that targeting METTL1 is an effective treatment against certain cancers, helping to kill cancer cells while leaving the other cells in the body untouched,” says Esteban Orellana, PhD, first author on the paper and a Pew and Damon Runyon Cancer Foundation fellow in the Gregory Lab. “This could mean that there would be fewer unpleasant side effects. The next step is to see if our encouraging results can be translated across to the clinic.”

Learn more about research at Dana-Farber/Boston Children’s.