In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 06 2024
18 06 2024
Historique:
received:
23
02
2024
accepted:
03
06
2024
medline:
18
6
2024
pubmed:
18
6
2024
entrez:
17
6
2024
Statut:
epublish
Résumé
In vitro evolution and whole genome analysis has proven to be a powerful method for studying the mechanism of action of small molecules in many haploid microbes but has generally not been applied to human cell lines in part because their diploid state complicates the identification of variants that confer drug resistance. To determine if haploid human cells could be used in MOA studies, we evolved resistance to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel) using a near-haploid cell line (HAP1) and then analyzed the genomes of the drug resistant clones, developing a bioinformatic pipeline that involved filtering for high frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound. Applying the filter to sequences from 28 drug resistant clones identified a set of 21 genes which was strongly enriched for known resistance genes or known drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, discovered and studied in an isogenic background.
Identifiants
pubmed: 38886371
doi: 10.1038/s41598-024-63943-7
pii: 10.1038/s41598-024-63943-7
doi:
Substances chimiques
Antineoplastic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
13989Subventions
Organisme : NIH HHS
ID : GM085764
Pays : United States
Informations de copyright
© 2024. The Author(s).
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