Scientists from Princess Margaret Cancer Centre have identified a new potential target for treating clear cell renal cell carcinoma (ccRCC), a kidney cancer that forms in the tubules that filter waste from blood.
This subtype of renal cell carcinoma is the most common type of kidney cancer and accounts for the majority of kidney cancer-related deaths. If detected early, surgery to remove tumours can be curative. However, for many patients, the cancer has spread by the time of diagnosis with disease reoccurrence being common after surgery.
Almost all cases of ccRCC involve the loss of an important gene called Von Hippel Lindau (VHL). Although the loss of this gene is necessary to drive tumour formation, its loss alone cannot initiate cancer. Recent studies have found that several other important genes are frequently damaged in this type of cancer. Interestingly, many of these genes are all involved in managing how DNA is packaged and controlled within cells—a process known as epigenetic regulation.
To examine this epigenetic link and find new treatment targets, the researchers screened a large library of chemical compounds, designed to interfere with various epigenetic regulators, in kidney cancer cells. One compound, called MS023, was able to reduce tumour growth. MS023 is an inhibitor of a protein known as PRMT1. This stood out as PRMT1 plays a critical role in regulating gene expression and responding to DNA damage.
Further analysis of PRMT1 in kidney cancer cells and pre-clinical models showed that it is key for cancer growth and impacts the cell cycle and DNA damage repair pathways. PRMT1 also interacts with RNA binding proteins and is important for producing messenger RNA—a key component of gene expression. When PRMT1 function is disrupted, it causes an accumulation of structures called R-loops, which, when present in excess, are abnormal formations in RNA/DNA that eventually lead to further DNA damage. As a result, cancer cells treated with MS023 become more vulnerable and struggle to survive.
These findings offer a promising new approach to treating kidney cancer, with PRMT1 emerging as a key target for future therapies. While still in the early stages, this research could pave the way for treatments that specifically target kidney cancer cells, potentially improving survival rates and offering new hope for patients.
The first author of this study is Dr. Joseph Walton, Postdoctoral Researcher at Princess Margaret Cancer Centre.
The senior author of this study is Dr. Laurie Ailles, Senior Scientist at Princess Margaret Cancer Centre. Dr. Ailles is also a Professor in the Department of Medical Biophysics at the University of Toronto.
This work was supported by the Cancer Research Society, Ontario Institute for Cancer Research, Government of Ontario, Canadian Urological Association in collaboration with Kidney
Cancer Research Network of Canada (KCRNC), and The Princess Margaret Cancer Foundation.
Walton J, Ng ASN, Arevalo K, Apostoli A, Meens J, Karamboulas C, St-Germain J, Prinos P, Dmytryshyn J, Chen E, Arrowsmith CH, Raught B, Ailles L. PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma. Nat Commun. 2024 Sep 19;15(1):8232. doi: 10.1038/s41467-024-52507-y. PMID: 39300069; PMCID: PMC11413393.