WRN May Be Key to Overcoming Colorectal Cancer Drug Resistance

WRN May Be Key to Overcoming Colorectal Cancer Drug Resistance

Targeting the genetic dependency Werner helicase (WRN) could open up treatment for drug resistant colorectal cancer (CRC), according to new research. The study used a large collection of colorectal cancer organoids with impaired mismatch DNA repair (60 unique models in total) and confirmed that inhibiting WRN using CRISPR reduced cancer cell growth. Notably, the study showed for the first time that cancer cells resistant to existing treatments, including chemotherapy, targeted therapies or immunotherapies, require WRN for survival.

Researchers from the Wellcome Sanger Institute, in collaboration with the Candiolo Cancer Institute in Italy, and the Netherlands Cancer Institute, collaborated on the study, which was published this week in Cancer Discovery.

Gabriele Picco, first author of the study and Postdoctoral Fellow at the Wellcome Sanger Institute, said: “Through international collaboration and having access to the largest collection of mismatch repair-deficient colorectal cancer models, we have built on previous research and shown that WRN dependency plays a key role in cancers resistant to existing treatments.  Developing these unique patient-derived models allows us also to understand more about the genetic alterations involved in WRN dependency, which is key to unveil the basis of this genetic vulnerability fully and to create effective medicines in the future.”

Their study suggests that developing novel drugs to target WRN could lead to new treatment options for those whose cancer no longer responds to other treatments. It also provides new insight into which tumors display WRN dependency. These results might allow clinicians to identify better those who could benefit from potential targeted drugs.

The results are one of the fruits of the Cancer Dependency Map, a project based at the Sanger Institute, which is a major initiative to provide a detailed rulebook of precision cancer treatments to help more patients receive effective therapies.

Mathew Garnett, co-senior author and group leader at the Wellcome Sanger Institute, said: “Understanding the weaknesses in cancers to help make precision medicine is the goal of the Cancer Dependency Map. This study has reinforced WRN as a target for drug development in colorectal cancer, with the possibility of it also being important in other cancers that show microsatellite instability. If these drugs can be developed and are shown to be successful, it would offer a new therapy to people whose cancer has become resistant to existing treatments.”

Faulty DNA mismatch repair leads to microsatellite instability, commonly seen in some types of cancers. In colorectal cancers, reportedly 10 to 15 per cent of cases display microsatellite instability.

Targeted therapies, chemotherapy, and immunotherapy are all used to treat CRC, however, the cancers can become resistant to these treatments, leaving a subset of patients without effective therapies.

Previous research led by Sanger scientists identified WRN as a possible treatment target in cancer cells with microsatellite instability. Further study, the scientists say, is required to develop WRN-targeted medicines and also to see if these therapies could be beneficial either instead of, or alongside current treatment.

The researchers also discovered that alterations in specific genes involved in mismatch repair were involved in WRN dependency. Understanding more about the genes involved in this pathway could lead to the identification of biomarkers that might determine which cancers would be most sensitive to blocking WRN.

Professor Emile Voest, co-author and medical oncologist and senior group leader at the Netherlands Cancer Institute and Oncode Institute, said: “Another interesting result from this study is that we found that specific MMR-pathway gene inactivation impacts WRN dependency. This provides insights into the mechanism of WRN dependency and may lead to distinguishing novel biomarkers for cancers that rely on the WRN gene, helping to identify those who would be most likely to benefit from WRN inhibitors, if they are developed.”