October 20, 2021

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Cancer Discovery: Identify new genetic drug targets for drug-resistant colorectal cancer

Cancer Discovery: Identify new genetic drug targets that are expected to help develop therapies for drug-resistant colorectal cancer

 

Cancer Discovery: Identify new genetic drug targets for drug-resistant colorectal cancer. Colorectal cancer, commonly known as bowel cancer, is the fourth most common type of cancer in the UK. Every year, about 42,300 individuals in the UK will be diagnosed with colorectal cancer.

Targeted therapies, chemotherapy and immunotherapy are usually used to treat colorectal cancer patients (CRC) with mismatch repair-deficient (dMMR)/microsatellite instability (MSI-H). However, the target The clinical therapeutic effect of tropism therapy and chemotherapy is often limited by the drug resistance of cancer cells and drug toxicity. About half of the patients receiving immunotherapy will develop resistance to immune checkpoint inhibitors. Werner syndrome is ATP-dependent. Deletion of WRN is a form of synthetic lethality in dMMR/MSI-H cells.

Cancer Discovery: Identify new genetic drug targets for drug-resistant colorectal cancer

Recently, a research report entitled “Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy and Immunotherapy” was published in the international journal Cancer Discovery, from the Institute of Sanger College, etc. Scientists at the institution have shown through research that targeting specific cancer survival genes may be expected to help develop new targeted therapies for the treatment of colorectal cancer.

In the article, researchers used advanced patient-derived organoid models to collect information about the genetic dependence of WRN in cancers that have developed resistance to standardized therapies. The researchers said that the development of new drugs that target WRN may be expected to help develop new therapies to treat cancer patients who do not respond to other therapies, and the relevant research results can also reveal which tumors will be WRN-dependent, and may be able to Allow clinicians to better identify which patients are more likely to benefit from potential targeted therapies.

The results of this article are based on the Cancer Dependency Map developed by scientists, which can provide an important measure to provide a detailed rule book for precise cancer therapy to help more patients with effective treatment. DNA mismatch repair (MMR) is a process in cells that recognizes and repairs errors that occur naturally during DNA replication. When this process is damaged, it will lead to microsatellite instability (due to insertions or base deletions). DNA replication inaccuracy), which is very common in many types of cancer. In colorectal cancer, about 10%-15% of patients will show microsatellite instability.

Cancer Discovery: Identify new genetic drug targets for drug-resistant colorectal cancer

Dependence profile of WRN in dMMR CRC preclinical model.

Image source: Gabriele Picco, et al. Cancer Discovery (2021). DOI: 10.1158/2159-8290.CD-20-1508

In previous studies, researchers found that WRN may be a potential target for new therapies to treat cancer cells carrying microsatellite instability. In this study, they used damaged mismatched DNA to repair the largest collection of colorectal cancer cells. After conducting research (a total of 60 and unique models), it was confirmed that WRN may reduce the growth of cancer cells through CRISPR technology; it is worth noting that for the first time, researchers have found that the current therapies (chemotherapy, targeted therapy or immunotherapy) produce Drug-resistant cancer cells may retain the survival requirements for WRN; therefore, it may be expected to be an important target for future drug therapy development, especially in the environment of some lethal diseases. In addition, researchers need to conduct in-depth research to develop WRN. Target drugs and observe whether these therapies can replace current therapies or be used in combination with them.

Researchers also found that changes in specific genes involved in mismatch repair may also be related to WRN dependence. Understanding the information of multiple genes involved in this pathway may help identify specific biomarkers and determine which cancers are Blocking WRN is very sensitive. Researcher Gabriele Picco pointed out that through international cooperation and obtaining the largest collection of colorectal cancer models with mismatch repair defects, we have now found based on previous studies that WRN dependence plays a role in cancers that are resistant to current therapies. It plays a key role, and the development of special patient-derived models can help scientists better understand the genetic changes involved in WRN dependence, which is critical for fully uncovering the basis of genetic susceptibility and developing new therapies.

 

Cancer Discovery: Identify new genetic drug targets for drug-resistant colorectal cancer

Dependence profile of WRN in dMMR CRC preclinical model.

Image source: Gabriele Picco, et al. Cancer Discovery (2021). DOI: 10.1158/2159-8290.CD-20-1508

If these special patient-derived organoids are not developed, researchers will not be able to obtain relevant research results, because these organoid models can help researchers investigate the genetic susceptibility of cancer that is resistant to multiple therapies; Drug-resistant cancers are often very challenging for researchers, and the development of new models may provide a way to help develop new therapies for the treatment of related cancers.

Another interesting finding in this paper is that the inactivation of specific MMR pathway genes may affect the dependence of WRN. This provides new insights for clarifying the mechanism of WRN dependence and can help effectively distinguish WRN-dependent genes. A new type of biomarker for cancer, and can help identify which patients will benefit from the treatment of WRN inhibitors.

In summary, the researchers said that understanding the weaknesses of cancer can help to carry out precise treatment or the goal of cancer dependence map development. The research in this article proposes that WRN may be used as a new target for the development of colorectal cancer drug therapy, and it is also important for research. Other cancers that exhibit microsatellite instability are also very important.

If related drugs can be successfully developed, they may be used as a new type of therapy to help treat cancer patients who are resistant to multiple current therapies.

 

 

 

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