Role of symmetric and asymmetric division of stem cells in developing drug resistance

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Abstract
Often, resistance to drugs is an obstacle to a successful treatment of cancer. In spite of the importance of the problem, the actual mechanisms that control the evolution of drug resistance are not fully understood. Many attempts to study drug resistance have been made in the mathematical modeling literature. Clearly, in order to understand drug resistance, it is imperative to have a good model of the underlying dynamics of cancer cells. One of the main ingredients that has been recently introduced into the rapidly growing pool of mathematical cancer models is stem cells. Surprisingly, this all-so-important subset of cells has not been fully integrated into existing mathematical models of drug resistance. In this work we incorporate the various possible ways in which a stem cell may divide into the study of drug resistance. We derive a previously undescribed estimate of the probability of developing drug resistance by the time a tumor is detected and calculate the expected number of resistant cancer stem cells at the time of tumor detection. To demonstrate the significance of this approach, we combine our previously undescribed mathematical estimates with clinical data that are taken from a recent six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myelogenous leukemia. Based on our analysis we conclude that leukemia stem cells must tend to renew symmetrically as opposed to their healthy counterparts that predominantly divide asymmetrically.