New strategies for targeting common cancers

A study published in eLife showed that targeting a protein called WRN (Werner Syndrome Helicase) is expected to treat patients with high microsatellite instability tumors.

Microsatellite instability (MSI) refers to the loss of DNA mis-insertion and deletion due to loss of mismatch repair (MMR) gene function. Compared to normal tissues, MSI tumor microsatellite sequence growth or truncation is one of the characteristics of DNA repair defective tumor cells.

Since it was discovered in hereditary nonpolyposis and rectal cancer in 1993, MSI has been detected in various cancers such as endometrial cancer, esophageal cancer, and lung cancer. In May 2017, the FDA approved the PD-L1 immunosuppressant, Pabloizumab, for the treatment of unresectable or metastatic solid tumors with MSI-H or mismatch repair defects (dMMR). The first cancer treatment method that does not target tumor types, but targets tumor markers, has epoch-making significance in the history of cancer treatment.

Immunotherapy, such as pembrolizumab, nivolumab and ipilimumab transformed the treatment of MSI-H tumors. Although these drugs often cause long-term positive reactions in MSI-H cancer patients, the ultimate resistance to immunotherapy means that more effective treatments are still needed.

Simon Wöhrle, a chief scientist at the Boehringer Ingelheim Regional Center (RCV) in Vienna, Austria, believed that targeted cancer therapies should be based on biological systems that rely on tumor cells rather than healthy tissue to survive. Therefore, we first need to understand what helps them survive and grow before developing new therapies for MSI-H cancer cells.

To find the answer to this question, the research team used MSI-H cancer cell analysis and recent cell line function screening data. They demonstrated that removing WRN from MSI-H cells prevents them from working properly and leads to cell division defects. Importantly, they found that WRN-deficient MSI-H cancer cell lines exhibit chromosomal breaks and genomic instability, suggesting that WRN is a novel vulnerability of MSI-H cells.

Previous studies have shown that WRN loss results in Werner Syndrome, premature aging associated with an increased lifetime risk of tumorigenesis. Contrary to the previously proposed view that WRN proteins play a key role in tumor suppression, current results show that WRN has a significant pro-survival function for specific cancer cells.

Researchers have demonstrated the ability to combine deep functional genomic screening data with tumor cell line analysis to determine new targets for oncology. The results of this study suggest that pharmacological inhibition of WRN function may be a novel targeted therapeutic strategy for MSI-H cancer, helping to meet the demand for more effective drugs.