Drug-induced resistance evolution necessitates less aggressive treatment.

Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified a...

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Autores principales:	Teemu Kuosmanen, Johannes Cairns, Robert Noble, Niko Beerenwinkel, Tommi Mononen, Ville Mustonen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ba08f29bd91c4066a56d33bb658e0f4b
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spelling	oai:doaj.org-article:ba08f29bd91c4066a56d33bb658e0f4b2021-12-02T19:57:43ZDrug-induced resistance evolution necessitates less aggressive treatment.1553-734X1553-735810.1371/journal.pcbi.1009418https://doaj.org/article/ba08f29bd91c4066a56d33bb658e0f4b2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009418https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies.Teemu KuosmanenJohannes CairnsRobert NobleNiko BeerenwinkelTommi MononenVille MustonenPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 9, p e1009418 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Teemu Kuosmanen Johannes Cairns Robert Noble Niko Beerenwinkel Tommi Mononen Ville Mustonen Drug-induced resistance evolution necessitates less aggressive treatment.
description	Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies.
format	article
author	Teemu Kuosmanen Johannes Cairns Robert Noble Niko Beerenwinkel Tommi Mononen Ville Mustonen
author_facet	Teemu Kuosmanen Johannes Cairns Robert Noble Niko Beerenwinkel Tommi Mononen Ville Mustonen
author_sort	Teemu Kuosmanen
title	Drug-induced resistance evolution necessitates less aggressive treatment.
title_short	Drug-induced resistance evolution necessitates less aggressive treatment.
title_full	Drug-induced resistance evolution necessitates less aggressive treatment.
title_fullStr	Drug-induced resistance evolution necessitates less aggressive treatment.
title_full_unstemmed	Drug-induced resistance evolution necessitates less aggressive treatment.
title_sort	drug-induced resistance evolution necessitates less aggressive treatment.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/ba08f29bd91c4066a56d33bb658e0f4b
work_keys_str_mv	AT teemukuosmanen druginducedresistanceevolutionnecessitateslessaggressivetreatment AT johannescairns druginducedresistanceevolutionnecessitateslessaggressivetreatment AT robertnoble druginducedresistanceevolutionnecessitateslessaggressivetreatment AT nikobeerenwinkel druginducedresistanceevolutionnecessitateslessaggressivetreatment AT tommimononen druginducedresistanceevolutionnecessitateslessaggressivetreatment AT villemustonen druginducedresistanceevolutionnecessitateslessaggressivetreatment
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Drug-induced resistance evolution necessitates less aggressive treatment.

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