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Abstract Drug resistance poses a significant challenge in cancer treatment. Despite the initial effectiveness of therapies such as chemotherapy, targeted therapy and immunotherapy, many patients eventually develop resistance. To gain deep insights into the underlying mechanisms, single-cell profiling has been performed to interrogate drug resistance at cell level. Herein, we have built the DRMref database (https://ccsm.uth.edu/DRMref/) to provide comprehensive characterization of drug resistance using single-cell data from drug treatment settings. The current version of DRMref includes 42 single-cell datasets from 30 studies, covering 382 samples, 13 major cancer types, 26 cancer subtypes, 35 treatment regimens and 42 drugs. All datasets in DRMref are browsable and searchable, with detailed annotations provided. Meanwhile, DRMref includes analyses of cellular composition, intratumoral heterogeneity, epithelial–mesenchymal transition, cell–cell interaction and differentially expressed genes in resistant cells. Notably, DRMref investigates the drug resistance mechanisms (e.g. Aberration of Drug’s Therapeutic Target, Drug Inactivation by Structure Modification, etc.) in resistant cells. Additional enrichment analysis of hallmark/KEGG (Kyoto Encyclopedia of Genes and Genomes)/GO (Gene Ontology) pathways, as well as the identification of microRNA, motif and transcription factors involved in resistant cells, is provided in DRMref for user’s exploration. Overall, DRMref serves as a unique single-cell-based resource for studying drug resistance, drug combination therapy and discovering novel drug targets.
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A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies
Inevitably, almost all cancer patients develop resistance to targeted therapy. Intratumour heterogeneity is a major cause of drug resistance. Mathematical models that explain experiments quantitatively are useful in understanding the origin of intratumour heterogeneity, which then could be used to explore scenarios for efficacious therapy. Here, we develop a mathematical model to investigate intratumour heterogeneity in breast cancer by exploiting the observation that HER2+ and HER2− cells could divide symmetrically or asymmetrically. Our predictions for the evolution of cell fractions are in quantitative agreement with single-cell experiments. Remarkably, the colony size of HER2+ cells emerging from a single HER2− cell (or vice versa), which occurs in about four cell doublings, also agrees with experimental results, without tweaking any parameter in the model. The theory explains experimental data on the responses of breast tumours under different treatment protocols. We then used the model to predict that, not only the order of two drugs, but also the treatment period for each drug and the tumour cell plasticity could be manipulated to improve the treatment efficacy. Mathematical models, when integrated with data on patients, make possible exploration of a broad range of parameters readily, which might provide insights in devising effective therapies.
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- Award ID(s):
- 1708128
- PAR ID:
- 10382586
- Date Published:
- Journal Name:
- Journal of The Royal Society Interface
- Volume:
- 19
- Issue:
- 186
- ISSN:
- 1742-5662
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1098/rsif.2021.0803
