Key mutations discovered in cancer cells linked to WRN inhibitor resistance

Researchers have discovered key mutations in certain cancer cells that make them resistant to WRN inhibitors, a new class of anti-cancer drugs. The yet-to-be-published findings are presented on Friday at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

Werner helicase (WRN) inhibitors are already being evaluated in phase I clinical trials in patients with tumours that have microsatellite instability (MSI) – a condition in which the genes responsible for monitoring and repairing mistakes in DNA replication stop functioning, and errors are introduced. This is also called mismatch repair deficiency. MSI occurs in several cancers, including 20% of bowel and stomach cancers.

In 2019, a team at the Wellcome Sanger Institute, Cambridge, UK, led by Dr Mathew Garnett and including Dr Gabriele Picco as one of the first authors of the study, identified a protein in cancer cells, WRN, as being a vulnerability in MSI cancers. Since then, the team have shown that cancers resistant to standard-of-care therapies, including immunotherapy, rely heavily on WRN for survival.

Dr. Gabriele Picco, senior staff scientist and project lead in Dr Garnett's lab, told the Symposium: "WRN inhibitors function through a mechanism called synthetic lethality, where two non-lethal genetic events cause cell death when combined. MSI cancer cells, which have a defect in DNA repair, become dependent on WRN for survival. When WRN is inhibited, these cells cannot repair DNA damage, leading to their death, while healthy cells remain unaffected."

The team identified the first WRN inhibitor effective against cancer cells in laboratory tests earlier this year, and shortly after, two additional inhibitors were reported, which are now in clinical trials for MSI cancers, including colorectal (bowel) cancer. However, MSI cancers can develop resistance to WRN inhibitors.

Dr. Picco said: "Using advanced genetic screening and drug testing, our new study explores how colorectal cancer cells adapt to WRN inhibition and develop resistance, which is key for designing more effective therapies. After prolonged exposure to WRN inhibitors, we found that some cells acquired mutations in the WRN gene, the target of the drugs, rendering the drugs unable to bind and act on WRN effectively, allowing the cancer cells to survive.

"These mutations in the WRN gene highlight a novel resistance mechanism and provide a way for us to test the efficacy of alternative WRN inhibitors that might be able to overcome this resistance."

Speaking before the Symposium, Dr. Garnett said: "Our findings suggest that strategies that combine different drugs may be required to overcome resistance, including chemotherapy or immunotherapy. Moreover, approaches based on switching to alternative WRN inhibitors, including next-generation WRN inhibitors, might be also considered when resistance occurs. These results warrant further validation to advance clinical applications but have potential to inform clinical strategies and guide future treatment options."

The findings might also enable clinicians to check how patients' cancers are responding to a particular WRN inhibitor by means of liquid biopsies. These analyse patient blood samples to detect any cancer cells and DNA circulating in the blood stream. 

"Tracking resistance mutations via liquid biopsy could be a potential strategy for monitoring treatment response," said Dr. Picco.

The team are now carrying out drug cross-resistance studies, which investigate whether MSI cancers that are resistant to one type of WRN inhibitor might also be resistant to others.

"We are exploring combination strategies and identifying alternative drug targets to address resistance," he concluded.

Dr. Tim Greten, senior investigator at the Center for Cancer Research, National Cancer Institute, USA, is co-chair of the EORTC-NCI-AACR Symposium and was not involved in the research. He commented: "The work that this group is carrying out into the mechanisms of WRN inhibitor resistance is an important step forward in this field. Although WRN inhibitors are a new class of anti-cancer drug, we are already seeing that cancer cells are able to develop resistance to them, enabling tumours to start growing again. Working out ways to prevent this from happening will be important in MSI cancers, which include some colorectal, stomach, endometrial and ovarian cancers."