Exploring gene knockout strategies to identify potential drug targets using genome-scale metabolic models

Research on new cancer drugs is performed either through gene knockout studies or phenotypic screening of drugs in cancer cell-lines. Both of these approaches are costly and time-consuming. Computational framework, e.g., genome-scale metabolic models (GSMMs), could be a good alternative to find pote...

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Bibliographic Details
Published in:Scientific reports 2021-01, Vol.11 (1), p.213-213, Article 213
Main Authors: Paul, Abhijit, Anand, Rajat, Karmakar, Sonali Porey, Rawat, Surender, Bairagi, Nandadulal, Chatterjee, Samrat
Format: Article
Language:English
Subjects:
631/114
631/553
639/705
Cancer
Cell Line
Cell proliferation
Computer applications
Drug screening
Gene Knockout Techniques
Genomes
Genomics
Growth rate
Humanities and Social Sciences
Humans
Metabolism
Metabolism - drug effects
Metabolism - genetics
Models, Biological
Molecular Targeted Therapy
multidisciplinary
Science
Science (multidisciplinary)
Therapeutic targets
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Summary:Research on new cancer drugs is performed either through gene knockout studies or phenotypic screening of drugs in cancer cell-lines. Both of these approaches are costly and time-consuming. Computational framework, e.g., genome-scale metabolic models (GSMMs), could be a good alternative to find potential drug targets. The present study aims to investigate the applicability of gene knockout strategies to be used as the finding of drug targets using GSMMs. We performed single-gene knockout studies on existing GSMMs of the NCI-60 cell-lines obtained from 9 tissue types. The metabolic genes responsible for the growth of cancerous cells were identified and then ranked based on their cellular growth reduction. The possible growth reduction mechanisms, which matches with the gene knockout results, were described. Gene ranking was used to identify potential drug targets, which reduce the growth rate of cancer cells but not of the normal cells. The gene ranking results were also compared with existing shRNA screening data. The rank-correlation results for most of the cell-lines were not satisfactory for a single-gene knockout, but it played a significant role in deciding the activity of drug against cell proliferation, whereas multiple gene knockout analysis gave better correlation results. We validated our theoretical results experimentally and showed that the drugs mitotane and myxothiazol can inhibit the growth of at least four cell-lines of NCI-60 database.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-80561-1