Drug screening and CRISPR can be combined to help make a better anti-cancer drugs

a new study to create the most comprehensive analysis to understand anti-cancer drugs and how at the molecular level play a role. The Wellcome Sanger Institute(Wellcome Sanger Institute), the EMBL European Bioinformatics Institute(EMBL-EBI)and AstraZeneca(AstraZeneca)scientists across hundreds of cancer cell line drug response data with the CRISPR genetic screening combined to better understand exactly how drugs targeting cancer cells.

this study published in the molecular systems biology research to determine the 397 species affected by the test drug in 50%of mechanism of action. To support the drug of the reaction of the biological mechanisms of this better understanding will help more quickly and effectively develop new cancer drugs, and brings us closer to that for cancer patients the precision of the drug.

historically, the drug development success rate has been very low, only less than 10% of the desired compound can be used in clinical trials.

drugs to kill cancer cells, the exact mechanism(which mechanism of action)may at the molecular level is not yet fully understood, which means that it may not work as expected. When the drug is designed to target cancer cells due to DNA genetic changes caused by a specific weakness, which is particularly problematic. Some of the drugs targeting a variety of proteins, and for patients with more toxicity. Other drug efficacy is insufficient, and therefore can not effectively kill the cancer.

but in recent years, several new methods to help improve drug candidate success rate. Such as cancer the dependency graph(Cancer DepMap)such initiatives have created from the patient’s tumor cancer cells model of the reference collection, the reference model can be grown in the laboratory and widely used in the study. These cells model the A use is for the pharmacological screening, the screening test anti-cancer drug activity, to identify a specific cancer to a specific compound sensitivity.

another major breakthrough is the CRISPR-Cas9 technology development, the technology can edit cancer cell lines of genes, which one by one off to measure them for cancer the key to survival sex.

in the new study, researchers for the first time the CRISPR-Cas9 screening and pharmacological screening using a combination of the 484 species of cancer cell lines of the 397 unique anti-cancer compounds. Compounds include FDA-approved anticancer drug, the clinical development of the drug and the early development of the compound.

the team search through 484 cell lines in the two data sets the Association between the studied drug sensitivity with CRISPR knock-out drug targets corresponding to the degree. They determine the drug response and the genetic dependence between the 865 an important Association.

Wellcome to the University Sanger Institute first author Emmanuel Gonsalves(EmanuelGonçalves)Dr. said:“the knockout of the gene effect and the inhibition of gene to produce the protein the effect is not necessarily the same thing. Or function and Drug Response data and CRISPR screening data are relevant, which brings us to how drugs on the molecular level play a role with a more clear understanding, and be able to detect the drug when not working as we expected as work.”

the research team can determine how drugs kill up to 50%of the test compound in the cancer cells. Although there is no method to determine about half of the tested drug mechanism of action, but this does not mean that these compounds useless. May need more knowledge to fully understand how they at the molecular level play a role.

the study also yielded some surprising results, for example, breast cancer cell line MCL1 and MARCH5 gene is the Association between. MCL1 is usually in human cancers has changed, and with chemotherapy and relapse resistance related. At the same time dependent on MARCH5 and MCL1 in breast cancer cell lines, designed for targeting MCL1 protein to inhibit its activity of the drug is more effective.

EMBL European Bioinformatics Institute(EMBL-EBI)of the Aldo Segura-Cabrera, Dr. said:“a comprehensive understanding of the involved molecular pathways is to understand drugs and why a patient’s cancer play a role while the other patient’s cancers do not play a role of key. MARCH5 for example, in breast cancer MCL1 and MCL1 implies that we are not yet aware of the important molecular relationships. This antiCome and help us to understand the MCL1 protein inhibitors mechanism of action, as well as in some cancer cases, these drugs will be effective.”

to support the drug of the reaction of the biological mechanisms and the occurrence of the genomic background of a more comprehensive understanding will help researchers identify new biomarkers guiding drug combination therapy and anti-cancer drug resistance.

Wellcome to the University Sanger Institute, the papers senior author Matthew Garrett“says Dr. precision medicine one of the key challenges is to understand what kinds of drug for a particular patient most effective. The key step is to really understand the drug in the cells in the role. By such a large scale pharmacological and CRISPR screening combined, it gives us about how drugs work and at what kinds of cancer types unparalleled insights. This work brings us closer to precision cancer medicine.”