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  Dynamics of resistance development to imatinib under increasing selection pressure: a combination of mathematical models and in vitro data

Werner, B., Lutz, D., Brümmendorf, T. H., Traulsen, A., & Balabanov, S. (2011). Dynamics of resistance development to imatinib under increasing selection pressure: a combination of mathematical models and in vitro data. PLoS ONE, 6(12): e28955. doi:10.1371/journal.pone.0028955.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-D36C-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-D36D-0
Genre: Journal Article

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 Creators:
Werner, Benjamin1, Author              
Lutz, David, Author
Brümmendorf, Tim H., Author
Traulsen, Arne1, Author              
Balabanov, Stefan, Author
Affiliations:
1Research Group Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445641              

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 Abstract: In the last decade, cancer research has been a highly active and rapidly evolving scientific area. The ultimate goal of all efforts is a better understanding of the mechanisms that discriminate malignant from normal cell biology in order to allow the design of molecular targeted treatment strategies. In individual cases of malignant model diseases addicted to a specific, ideally single oncogene, e.g. Chronic myeloid leukemia (CML), specific tyrosine kinase inhibitors (TKI) have indeed been able to convert the disease from a ultimately life-threatening into a chronic disease with individual patients staying in remission even without treatment suggestive of operational cure. These developments have been raising hopes to transfer this concept to other cancer types. Unfortunately, cancer cells tend to develop both primary and secondary resistance to targeted drugs in a substantially higher frequency often leading to a failure of treatment clinically. Therefore, a detailed understanding of how cells can bypass targeted inhibition of signaling cascades crucial for malignant growths is necessary. Here, we have performed an in vitro experiment that investigates kinetics and mechanisms underlying resistance development in former drug sensitive cancer cells over time in vitro. We show that the dynamics observed in these experiments can be described by a simple mathematical model. By comparing these experimental data with the mathematical model, important parameters such as mutation rates, cellular fitness and the impact of individual drugs on these processes can be assessed. Excitingly, the experiment and the model suggest two fundamentally different ways of resistance evolution, i.e. acquisition of mutations and phenotype switching, each subject to different parameters. Most importantly, this complementary approach allows to assess the risk of resistance development in the different phases of treatment and thus helps to identify the critical periods where resistance development is most likely to occur.

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Language(s): eng - English
 Dates: 2011-12-22
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: eDoc: 576466
DOI: 10.1371/journal.pone.0028955
Other: 2887/S 39231
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Title: PLoS ONE
Source Genre: Journal
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Pages: - Volume / Issue: 6 (12) Sequence Number: e28955 Start / End Page: - Identifier: ISSN: 1932-6203 (online)