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New genetic drug target for treatment resistant colorectal cancer

19 April 2021
Appeared in BioNews 1091

A new potential drug target for treating some types of colorectal cancers has been identified.

A particular subset of colorectal cancers diagnosed as 'mismatch repair-deficient, microsatellite instability-high' can be affected by resistance to some treatments, meaning that new targets for drugs are needed to cure patients who have this form of cancer. An international collaborative study looked at a gene that cancer cells in these resistant forms of cancer depend on to survive: the Werner Helicase (WRN) gene. Researchers developed cell lines and organoids from 60 individual patients' tumours and lesions and used CRISPR/Cas9 to knock out the WRN gene in some of these, to investigate its function. 

'The development of these unique patient organoid models allowed us to investigate this genetic weakness in cancers that had acquired resistance to target therapies, chemotherapy and immunotherapy. Cancers that are resistant to treatments can be challenging to treat, and having models that provide a way to investigate new therapies for these is crucial if we are to find ways to continue to help people with advanced disease,' said Professor Alberto Bardelli, director of laboratory molecular oncology at the Candiolo Cancer Institute in Italy and co-author of the study. 

The study published in Cancer Discovery built on previous research, as WRN had been identified as a possible treatment target in cancer cells with microsatellite instability by researchers at the Wellcome Sanger Institute in Cambridge. It had been discovered as part of the Cancer Dependency Map project run by the Sanger which aims to discover the genes different cancers depend on for survival. 

Microsatellite instability is a condition resulting from the impairment of DNA mismatch repair-deficiency, a process in which cells recognise and repair naturally occurring mistakes during DNA replication. Impairment of this process results in incorrect DNA replication which can lead to several types of cancer. Notably, colorectal cancer has been reported to display microsatellite instability in about 15 percent of cases. 

'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.' said Dr Mathew Garnett, co-senior author and group leader at the Sanger.

The study provides new insights into how specific genes undergoing mismatch repair-deficiency are involved in WRN dependency which, according to Professor Emile Voest, co-author and senior group leader at the Netherlands Cancer Institute, 'may lead to distinguishing novel biomarkers for cancers that rely on the WRN gene', which would allow doctors to identify patients who will benefit from treatment that targets it. 

Cancer Dependency Map
Sanger Institute |  17 October 2021
New genetic drug target for treatment resistant colorectal cancer
Wellcome Sanger Institute |  12 April 2021
Werner helicase is a synthetic-lethal vulnerability in mismatch repair-deficient colorectal cancer refractory to targeted therapies, chemotherapy and immunotherapy
Cancer Discovery |  9 April 2021
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