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A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics.

ABSTRACT: Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, where ~50% of high-risk patients do not survive. Our screen examines all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest existing drug combination screens. Using dense drug-drug rescreening, we find that the top CRISPR-nominated drug combinations are more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discover that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using patient-derived xenograft (PDX) models. Our findings provide a valuable resource and demonstrate the feasibility of using targeted CRISPR knockout to discover combinations with common chemotherapeutics, a methodology with application across all cancers.

SUBMITTER: Lee HM

PROVIDER: S-EPMC10643606 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics.

Lee Hyeong-Min HM Wright William C WC Pan Min M Low Jonathan J Currier Duane D Fang Jie J Singh Shivendra S Nance Stephanie S Delahunty Ian I Kim Yuna Y Chapple Richard H RH Zhang Yinwen Y Liu Xueying X Steele Jacob A JA Qi Jun J Pruett-Miller Shondra M SM Easton John J Chen Taosheng T Yang Jun J Durbin Adam D AD Geeleher Paul P

Nature communications 20231113 1

Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, wher ...[more]

PMID: 37957169

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Project description:ObjectivesThe study aimed at identifying the commonly used non-prescribed antibiotics (NPAs) and the main health conditions leading to the practices of self-medication with antibiotics (SMAs) in Maputo city, Mozambique.DesignCross-sectional qualitative study based on individual and group interviews.SettingThe study was conducted in nine pharmacies of three socioeconomic areas of Maputo city, from October 2018 to March 2019.ParticipantsThe study included 32 pharmacy clients and 17 pharmacists. The pharmacy clients included men 10 (31%) and women 22 (69%) ranging from 19 to 67 years while the pharmacists included men 6 (35,3%) and women 11 (64,7%) with ages ranging from 24 to 47 years.FindingsThe majority of the pharmacy clients 30 (93.75%) admitted frequent use of NPAs, 15 (88.2%) out of the 17 pharmacists admitted dispensing NPAs. While the majority of the participants (16) mentioned the use of amoxicillin, also known as 'two colours medicine', 14 mentioned the use of cotrimoxazole and seven mentioned amoxicillin with clavulanic acid. Two to five participants also used tetracycline, ciprofloxacin, azithromycin, doxycycline, erythromycin, metronidazole and phenoxymethylpenicillin. The above mentioned NPAs were used to treat self-perceived sore throat, fever, pain, cough, vaginal discharge, eye problems, the common influenza, urinary infections, respiratory tract infections, wounds and toothaches.ConclusionsAntibiotics are perceived as essential medical resources to manage health and illnesses. While taking an active role in their health-disease process, participants commonly used amoxicillin, 'two colours', cotrimoxazole and amoxicillin with clavulanic acid to manage their health and that of their families. In this sense, the practices of SMAs were perceived as part of the self-care process and not necessarily as misuse of antibiotics. A wideunderstanding of health-seeking beliefs and behaviours regarding the utilisation of antibiotics is needed to inform public health experts, health policymakers and other stake-holders in designing and implementing public health education and health promotion programsat all levels in Mozambique.

Project description:Ethnopharmacological relevanceAccording to Traditional Chinese Medicine theory, influenza is categorized as a warm disease or Wen Bing. The Wen Bing formulas, such as Yin-Qiao-San and Sang-Ju-Yin, are still first-line herbal therapies in combating variant influenza virus. To continue our study on the pharmacokinetic and pharmacodynamic interactions between Wen Bing formulas and oseltamivir (OS), the first-line western drug for the treatment of influenza, further interactions between OS and the eight single herbs and their relevant marker components from Wen Bing formulas were investigated in the current study.Aim of studyTo establish an in-vitro screening platform for investigation of the potential anti-influenza herbs/herbal components that may have pharmacokinetic and pharmacodynamic interactions with OS.Materials and methodsTo screen potential inhibition on OS hydrolysis, 1 μg/mL of OS is incubated with herbs/herbal components in diluted rat plasma, microsomes and human recombinant carboxylesterase 1(hCE1) under optimized conditions. MDCK-WT and MDCK-MDR1 cell lines are utilized to identify potential modification on P-gp mediated transport of OS by herbs/herbal components. Caco-2 cells with and without Gly-Sar inhibition are performed to study the uptake of OS via PEPT1 transporters. Modification on OAT3 mediated transport is verified by the uptake of OS on HEK293-MOCK/HEK293-OAT3 cells. Anti-virus effects were evaluated using plaque reduction assay on H1N1 and H3N2 viruses. Potential pharmacokinetic and pharmacodynamic interaction between OS (30 mg/kg) and the selected herb, Radix Scutellariae (RS), at 300-600 mg/kg were carried out on rats. All samples are analyzed by an LC/MS/MS method for the contents of OS and OSA. A mechanistic PK model was developed to interpret the HDI between OS and RS in rats.ResultsOur developed platform was successfully applied to screen the eight herbal extracts and their ten marker components on metabolic inhibition of OS and modification of OS transport mediated by P-gp, OAT3 and PEPT1. Results from six in-vitro experiments were analyzed after converting raw data from each experiment to corresponding fold-change (FC) values, based on which Radix Scutellariae (RS) were selected to have the most HDI potential with OS. By analyzing the plasma and urine pharmacokinetic data after co-administration of OS with a standardized RS extract in rats using an integrated population pharmacokinetics model, it is suggested that RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which leads to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine. Never the less, the anti-virus effects of 2.5 h post-dose rat plasma were not influenced by co-administration of OS with RS.ConclusionA six-dimension in-vitro screening platform has been developed and successfully applied to find RS as a potential herb that would influence the co-administrated OS in rats. Although co-administered RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which lead to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine, the anti-virus effect of OS was not influenced by co-administered RS.

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A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics.

Publications

A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics.

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