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Open Access 01-12-2019 | Tyrosine Kinase Inhibitors | Research article

Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia

Authors: H. Jonathan G. Lindström, Astrid S. de Wijn, Ran Friedman

Published in: BMC Cancer | Issue 1/2019

Abstract

Background

Resistance towards targeted cancer treatments caused by single nucleotide variations is a major issue in many malignancies. Currently, there are a number of available drugs for chronic myeloid leukaemia (CML), which are overcome by different sets of mutations. The main aim of this study was to explore if it can be possible to exploit this and create a treatment protocol that outperforms each drug on its own.

Methods

We present a computer program to test different treatment protocols against CML, based on available resistance mutation growth data. The evolution of a relatively stable pool of cancer stem cells is modelled as a stochastic process, with the growth of cells expressing a tumourigenic protein (here, Abl1) and any emerging mutants determined principally by the drugs used in the therapy.

Results

There can be some benefit to Bosutinib-Ponatinib rotation therapy even if the mutation status is unknown, whereas Imatinib-Nilotinib rotation is unlikely to improve the outcomes. Furthermore, an interplay between growth inhibition and selection effects generates a non-linear relationship between drug doses and the risk of developing resistance.

Conclusions

Drug rotation therapy might be able to delay the onset of resistance in CML patients without costly ongoing observation of mutation status. Moreover, the simulations give credence to the suggestion that lower drug concentrations may achieve better results following major molecular response in CML.

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Title: Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia
Authors: H. Jonathan G. Lindström
Astrid S. de Wijn
Ran Friedman
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Tyrosine Kinase Inhibitors
Targeted Therapy
Tyrosine Kinase Inhibitors
Bosutinib
Imatinib
Nilotinib
Ponatinib
Chronic Myeloid Leukemia
Published in: BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-019-5690-5

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