Drug-induced resistance evolution necessitates less aggressive treatment

• DOI: 10.1371/journal.pcbi.1009418
• Publication Date: 2021-09-24T14:36:37Z
• Authors: Teemu Kuosmanen; Johannes Cairns; Robert Noble; Niko Beerenwinkel; Tommi Mononen; Ville Mustonen
• Keywords: 0301 basic medicine; QH301-705.5; Antineoplastic Agents; Models, Biological; RC0254; Evolution, Molecular; 03 medical and health sciences; Anti-Infective Agents; Mutation Rate; Neoplasms; Humans; Computer Simulation; Biology (General); QA; Biochemistry, cell and molecular biology; Stochastic Processes; 0303 health sciences; Computer and information sciences; Dose-Response Relationship, Drug; Host Microbial Interactions; Computational Biology; Drug Resistance, Microbial; CHEMOTHERAPY; RESCUE; 3. Good health; Phenotype; Drug Resistance, Neoplasm; CELLS; Mutation; Cancers; RC; Research Article

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.