Treatment scheduling effects on the evolution of drug resistance in heterogeneous cancer cell populations.
Journal
NPJ breast cancer
ISSN: 2374-4677
Titre abrégé: NPJ Breast Cancer
Pays: United States
ID NLM: 101674891
Informations de publication
Date de publication:
26 May 2021
26 May 2021
Historique:
received:
15
05
2020
accepted:
19
04
2021
entrez:
27
5
2021
pubmed:
28
5
2021
medline:
28
5
2021
Statut:
epublish
Résumé
The effect of scheduling of targeted therapy combinations on drug resistance is underexplored in triple-negative breast cancer (TNBC). TNBC constitutes heterogeneous cancer cell populations the composition of which can change dynamically during treatment resulting in the selection of resistant clones with a fitness advantage. We evaluated crizotinib (ALK/MET inhibitor) and navitoclax (ABT-263; Bcl-2/Bcl-xL inhibitor) combinations in a large design consisting of 696 two-cycle sequential and concomitant treatment regimens with varying treatment dose, duration, and drug holiday length over a 26-day period in MDA-MB-231 TNBC cells and found that patterns of resistance depend on the schedule and sequence in which the drugs are given. Further, we tracked the clonal dynamics and mechanisms of resistance using DNA-integrated barcodes and single-cell RNA sequencing. Our study suggests that longer formats of treatment schedules in vitro screening assays are required to understand the effects of resistance and guide more realistically in vivo and clinical studies.
Identifiants
pubmed: 34040000
doi: 10.1038/s41523-021-00270-4
pii: 10.1038/s41523-021-00270-4
pmc: PMC8154902
doi:
Types de publication
Journal Article
Langues
eng
Pagination
60Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
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