Cancer Discovery: Finding the weakness of drug-resistant colorectal cancer: WRN gene is expected to become a new target for the treatment of drug-resistant colorectal cancer

DNA mismatch repair (dMMR) can identify and repair spontaneously mismatched bases during DNA replication.

Werner helicase (WRN) is a synthetic lethal target for dMMR/MSI-H cancer and has a large proportion of sensitivity in colorectal cancer cell lines.

Recently, Dr.

The study performed WRN gene knockout in 60 experimental models of drug-resistant colorectal cancer, proving that WRN dependence is a prominent feature of drug-resistant colorectal cancer, and showing WRN for dMMR/MSI-H colorectal cancer patients The therapeutic potential of genes, targeting WRN genes is expected to help develop new targeted therapies for the treatment of drug-resistant colorectal cancer.

In this study, the authors collected the largest dMMR colorectal cancer preclinical model to date, including 60 unique models from primary tumors and metastatic lesions (such as cancer cell lines and patient-derived 3D organ cultures).

In order to verify the WRN dependence in the case of drug resistance, the authors performed WRN dependence tests on multiple cell lines from patients with dual or triple therapy resistance, and found that the knockout of WRN resulted in chromosomal abnormalities and significantly reduced cancer cell The survival rate indicates that regardless of the tumor's mutational background and the treatment plan for obtaining drug resistance, dMMR-CRC cells resistant to clinically relevant targeted therapies or chemotherapy are still synthetically lethal to WRN.

Next, the authors used multiple patient-derived organoid models to investigate whether the poor response of dMMR-CRC tumors to immunotherapy depends on WRN.

In general, the authors studied the therapeutic potential of targeting WRN in preclinical models of dMMR colorectal cancer, and found that more than 90% of the models rely on WRN, supporting WRN as a single treatment or combined targeting of dMMR/MSI-H tumors Targets for drugs, chemotherapy or immunotherapy.

Original source:

Gabriele Picco, Chiara Maria Cattaneo, Esmee J.