Exploiting evolution to treat drug resistance: Combination therapy and the double bind

Abstract

Although many anti cancer therapies are successful in killing a large percentage of tumour cells when initially administered, the evolutionary dynamics underpinning tumour progression mean that often resistance is an inevitable outcome, allowing for new tumour phenotypes to emerge that are unhindered by the therapy. Research in the field of ecology suggests that an evolutionary double bind could be an effective way to treat tumours. In an evolutionary double bind two therapies are used in combination such that evolving resistance to one leaves individuals more susceptible to the other. In this paper we present a general evolutionary game theory model of a double bind to study the effect that such approach would have in cancer. Furthermore we use this mathematical framework to understand recent experimental results that suggest a synergistic effect between a p53 cancer vaccine and chemotherapy. Our model recapitulates the experimental data and provides an explanation for its effectiveness based on the commensalistic relationship between the tumour phenotypes.