Drug resistance in cancer: Principles of emergence and prevention

TLDR

Targeted therapies, such as imatinib that inhibits BCR‑ABL, have shown promise in cancers like chronic myeloid leukemia, yet drug resistance remains a major obstacle. The study develops a mathematical framework to investigate how resistance emerges and can be prevented in cancers treated with targeted small‑molecule drugs. The framework models tumor dynamics stochastically using measurable parameters such as cell turnover and mutant generation rates, and is applied to chronic myeloid leukemia. The model shows that resistance typically develops before treatment begins, that combination therapy offers little advantage over single drugs in high‑turnover cancers, yet a triple‑drug combination with distinct targets could potentially overcome resistance at later stages.

Abstract

Although targeted therapy is yielding promising results in the treatment of specific cancers, drug resistance poses a problem. We develop a mathematical framework that can be used to study the principles underlying the emergence and prevention of resistance in cancers treated with targeted small-molecule drugs. We consider a stochastic dynamical system based on measurable parameters, such as the turnover rate of tumor cells and the rate at which resistant mutants are generated. We find that resistance arises mainly before the start of treatment and, for cancers with high turnover rates, combination therapy is less likely to yield an advantage over single-drug therapy. We apply the mathematical framework to chronic myeloid leukemia. Early-stage chronic myeloid leukemia was the first case to be treated successfully with a targeted drug, imatinib (Novartis, Basel). This drug specifically inhibits the BCR-ABL oncogene, which is required for progression. Although drug resistance prevents successful treatment at later stages of the disease, our calculations suggest that, within the model assumptions, a combination of three targeted drugs with different specificities might overcome the problem of resistance.