Mol Syst Biol: Drug screening combined with CRISPR technology to improve 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, a breakthrough technology that discovers, removes, and replaces specific parts of DNA through a specially programmed enzyme called Cas9the technology is very precise, inexpensive, easy to use, and powerfula new study provides the most comprehensive analysis of the role of anticancer drugs at the molecular levelscientists at the Wellcome Foundation Sanger Institute in the UK, the European Bioinformatics Institute at the European Molecular Biology Laboratory (EMBL) and AstraZeneca Pharmaceuticals combined drug response data and CRISPR gene screening to investigate hundreds of cancer cells to better understand how drugs target themIn a study published July 6 in Molecular System biology,, researchers identified 50 percent of the 397 drugsthis further understanding of the biological mechanisms that support drug responses will help develop new cancer drugs faster and more effectively and bring us closer to precision treatment in cancer patientshistorically, the success rate of drug development has been low, with less than 10% of the expected compounds entering clinical trialsexact mechanism by which a drug kills cancer cells may not be entirely clear at the molecular level, meaning it may not work as expectedthis is especially tricky when a drug is designed to target specific weaknesses in cancer cells due to DNA genetic modificationssome drugs target a variety of proteins and are more toxic to patientsothers are not effective enough to effectively kill cancer cellsa summary of the illustration, but in recent years, some new methods have helped to increase the success rate of drug candidatesProjectssuch as the Cancer Dependence Map have created reference sets of cancer cell models from patient tumors that can grow in the lab and are widely used in researchone use of these cell models is for pharmacological screening, i.etesting the activity of anticancer drugs to determine the sensitivity of specific cancers to specific compounds Another major breakthrough in the drug sensitivity data set outlines is the development of CRISPR-Cas9, which edits genes in cancer cell lines and turns them off one by one to measure their importance to cancer survival the CRISPR-Cas9 dataset OutlineD In this new study, researchers for the first time combined CRISPR-Cas9 screening with pharmacological screening of 397 unique anticancer compounds in 484 cancer cells compounds include FDA-approved anticancer drugs, clinically developed drugs, and early-developed compounds studied the extent to which drug sensitivity corresponded to CRISPR knocking on drug targets by searching for associations between two data sets of 484 cell lines they identified a significant association between 865 drug reactions and gene dependence "Knocking out a gene and suppressing the effects of the protein produced by the gene is not necessarily the same," said Dr Emmanuel Gonvalves of the Wellcombe Sanger Institute, the first author of the study, the integration of drugs and CRISPR gene dependence in tumor cell lines But when a molecular pathway or function is associated with drug response data and CRISPR screening data, it gives us a clearer picture of how drugs work at the molecular level and the ability to detect when drugs don't work " the team was able to determine how the drug killed cancer cells in 50 percent of the compounds tested While the mechanism of action of about half of the drugs is uncertain, this does not mean that these compounds are useless more knowledge may be needed to fully understand how they work at the molecular level the study also found some surprising results, such as a link between the MCL1 and MARCH5 genes in breast cancer cell lines MCL1 usually changes in human cancer and is associated with chemotherapy resistance and recurrence in breast cancer cell lines that rely on both MARCH5 and MCL1, it is more effective to design drugs for MCL1 proteins that inhibit their activity "A full understanding of the molecular pathways involved is the key to understanding why one drug may be effective in one patient's cancer and not in another," said Dr Aldo Segura-Cabrera of the EMBL European Bioinformatics Institute, which is 's most significant example of the most significant associated drug category , for example, in breast cancer, the association between MARCH5 and MCL1 indicates an important molecular relationship that we do not realize this in turn helps us understand the mechanisms of MCL1 protein inhibitors and which cancer cases they are effective with " a more comprehensive understanding of the biological mechanisms and genomic contexts in which drug responses are supported will help researchers identify new biomarkers and guide drug combination therapies and drug resistance against cancer drugs "A key challenge for precision medicine is to understand what drugs are most effective for specific patients," said Dr Matthew Garnett, senior author of the paper , from the Sanger Institute at the Wellcome Trust in the UK 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 range, it provides us with unparalleled insights into how drugs work and the type of cancer work brings us closer to precise treatment of cancer "