Nature Sub-Journal: Drug screening combined with CRISPR technology to improve the efficacy of anti-cancer drugs.

Introduction: CRISPR comes from the immune system of microorganisms and is a game changer in the field of biological science. This breakthrough technology uses a specially programmed enzyme called cas9 to discover, remove and replace specific parts of DNA.the technology is very accurate, cheap, easy to use and powerful.a new study provides the most comprehensive analysis of the role of anticancer drugs at the molecular level.scientists from Wellcome Sanger Institute, EMBL and AstraZeneca have investigated hundreds of cancer cells by combining drug response data and CRISPR gene screening to better understand how drugs target cancer cells.in a study published on July 6 in molecular system biology, researchers identified 50% of 397 drugs.this further understanding of the biological mechanisms supporting drug response will help us develop new cancer drugs more quickly and effectively, and bring us closer to the precise treatment of cancer patients.historically, the success rate of drug development has been very low, with less than 10% of the expected compounds entering clinical trials.the exact mechanism by which a drug kills cancer cells may not be fully understood at the molecular level, which means that it may not function as expected.this is particularly difficult when a drug is designed to target specific weaknesses in cancer cells due to genetic changes in DNA.some drugs are targeted at a variety of proteins, which are more toxic to patients.others are not effective enough to kill cancer cells effectively.however, in recent years, some new methods have helped to improve the success rate of drug candidates.projects such as cancer dependency map have created reference sets of cancer cell models from patients' tumors, which can be grown in the laboratory and widely used in research.one of the uses of these cell models is for pharmacological screening, that is, testing the activity of anticancer drugs to determine the sensitivity of specific cancers to specific compounds.overview of drug sensitivity data set another major breakthrough is the development of crispr-cas9 technology, which can edit genes in cancer cell lines and turn them off one by one to measure their importance to cancer survival.CRISPR ‐ cas9 data set overview in this new study, researchers have for the first time combined crispr-cas9 screening with pharmacological screening of 397 unique anticancer compounds from 484 cancer cell lines.compounds include FDA approved anticancer drugs, clinically developed drugs and early developed compounds.by searching the association between two data sets of 484 cell lines, the corresponding degree of drug sensitivity and CRISPR knockout of drug targets was studied.they identified 865 significant associations between drug reactions and gene dependence.the integration of drug and CRISPR gene dependence in tumor cell lines, Dr. Emanuel gonvalves, from the welcom Sanger Institute and the lead author of the study, said: "the effect of knocking out a gene is not necessarily the same as the effect of inhibiting the protein produced by that gene.however, when a molecular pathway or function is associated with drug response data and CRISPR screening data, it gives us a clearer understanding of how drugs work at the molecular level and the ability to detect when drugs do not work."the team was able to determine how the drug killed 50% of the cancer cells in the compounds tested.although the mechanism of action of about half of the drugs is uncertain, it does not mean that these compounds are useless.more knowledge may be needed to fully understand how they work at the molecular level.this study also found some surprising results, such as the association between MCL1 and march5 genes in breast cancer cell lines.MCL1 is often altered in human cancers and is associated with chemotherapy resistance and recurrence.in breast cancer cell lines that depend on both march5 and MCL1, it is more effective to design drugs that inhibit MCL1 activity.a representative example of the most significant class of related drugs, Dr. Aldo Segura Cabrera of EMBL European Institute of bioinformatics, said, "a full understanding of the relevant molecular pathways is the key to understanding why one drug may be effective in one patient's cancer but not in another.for example, in breast cancer, the association between march5 and MCL1 indicates an important molecular relationship that we are not aware of.this in turn helps us understand the mechanism of action of MCL1 protein inhibitors and which cancer cases these drugs are effective."a more comprehensive understanding of the biological mechanisms supporting drug reactions and the genomic background of the reactions will help researchers identify new biomarkers, guide drug combination therapy and anti-cancer drug resistance.senior author of the paper, Dr. Matthew Garnett of the Sanger Institute of the welcom foundation in the UK, said: "one of the key challenges of precision medicine is to understand what drugs are most effective for specific patients.the key step is to really understand how a drug works in cells, which can be very difficult. by combining pharmacology and CRISPR screening in this context, it provides us with unparalleled insights into how drugs work and the types of cancer. this work brings us closer to the precise treatment of cancer. 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