Evolutionary dynamics of drug resistance

Ivana Bozic, Martin Nowak and colleagues modelled targeted therapy as a branching process in which resistance mutations arise before and during treatment. Their 2013 analysis showed that a tumour of a billion cells almost certainly carries cells resistant to any single drug, that monotherapy therefore fails predictably, and that two drugs without overlapping resistance mutations given together can cure where sequential use cannot, provided no single mutation confers cross-resistance. The framework explains the transient responses to single kinase inhibitors and underpins combination design, and later work added treatment holidays and dose modulation.