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

Author | xiao xia editor | Wang Cong typesetting | DNA Mismatch Repair (dMMR) can identify and repair spontaneously mismatched bases during DNA replication.
Microsatellite instability (MSI) is caused by damage to dMMR , Is a common phenomenon in cancer.
Thousands of MSI cancers are diagnosed every year around the world.
About 10-15% of sporadic colorectal cancer (CRC) show dMMR/MSI, which has implications for the prognosis and treatment of patients.
Significance.

Molecular targeted therapy and chemotherapeutics are used to treat patients with dMMR colorectal cancer.
Tumor evolution and drug resistance are the main causes of treatment failure and death in patients with colorectal cancer.

Therefore, although advances in precision medicine have improved the survival of patients with dMMR/MSI-H (high sensitivity) colorectal cancer, drug resistance will still develop.

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.

WRN is a member of the RecQ family of DNA helicases.
It plays an important but poorly understood role in maintaining genome stability, DNA repair, replication, transcription, and telomere maintenance.
A comprehensive assessment of WRN in colorectal cancer resistance is needed.
The role of sex.

Recently, Dr.
Mathew J Garnett from the Translational Cancer Genomics Group of the Wellcome Sanger Institute published a titled: Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy in Cancer Discovery, a top academic journal in the field of cancer.
and Immunotherapy research papers.

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).

Through CRISPR Cas9 and/or RNA interference WRN, clone formation test, gene and protein expression analysis, PCR and Western Blot experiments, the authors confirmed that inhibiting WRN has a lethal effect and strongly supports WRN as a therapeutic target and dMMR as a patient stratification Of biomarkers.

However, there is a rare subtype of dMMR/MSI-H colorectal cancer.
These subtypes are not dependent on WRN and may not be effective for WRN targeted therapy.

The WRN dependency map in the preclinical model of dMMR-CRC In order to verify the WRN dependency in the case of drug resistance, the authors performed WRN dependency tests on multiple cell lines from dual or triple therapy resistant patients and found that WRN was knocked out Causes chromosomal abnormalities and significantly reduces the survival rate of cancer cells, indicating that regardless of the tumor's mutation 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 Dependence.

The HCRC subline model derived from drug-resistant dMMR/MSI patients is WRN-dependent.
Next, the authors used multiple patient-derived organoid models to investigate whether the poor response of dMMR-CRC tumors to immunotherapy depends on WRN.

It was found that CRC-12 parent organoids were killed by autologous tumor-reactive T cells, but CRC-12-RES and CRC-12-B2M KO organoids were not affected by immune cells.

WRN knockout inhibited the activity of parental CRC-12 organoids and CRC-12-RES, indicating that a strong WRN dependency was retained in the model of autologous T cell-mediated cytotoxicity.

The dMMR-CRC model derived from immunotherapy ineffective patients is WRN-dependent.
In general, the authors studied the therapeutic potential of targeting WRN in a preclinical model of dMMR colorectal cancer, and found that more than 90% of the models are dependent on WRN, which supports WRN is used as a target for dMMR/MSI-H tumor monotherapy or combined with targeted drugs, chemotherapy or immunotherapy.

Link to the paper: https://cancerdiscovery.
aacrjournals.
org/content/early/2021/04/08/2159-8290.
CD-20-1508 Open for reprint