effect of cellular quiescence on the success of targeted cml therapy效应细胞静止目标cml治疗的成功.pdfVIP

Effect of Cellular Quiescence on the Success of Targeted CML Therapy Natalia L. Komarova1,2, Dominik Wodarz1,2* 1 Department of Mathematics, University of California Irvine, Irvine, California, United States of America, 2 Department of Ecology and Evolution, University of California Irvine, Irvine, California, United States of America Background. Similar to tissue stem cells, primitive tumor cells in chronic myelogenous leukemia have been observed to undergo quiescence; that is, the cells can temporarily stop dividing. Using mathematical models, we investigate the effect of cellular quiescence on the outcome of therapy with targeted small molecule inhibitors. Methods and Results. According to the models, the initiation of treatment can result in different patterns of tumor cell decline: a biphasic decline, a one-phase decline, and a reverse biphasic decline. A biphasic decline involves a fast initial phase (which roughly corresponds to the eradication of cycling cells by the drug), followed by a second and slower phase of exponential decline (corresponding to awakening and death of quiescent cells), which helps explain clinical data. We define the time when the switch to the second phase occurs, and identify parameters that determine whether therapy can drive the tumor extinct in a reasonable period of time or not. We further ask how cellular quiescence affects the evolution of drug resistance. We find that it has no effect on the probability that resistant mutants exist before therapy if treatment occurs with a single drug, but that quiescence increases the probability of having resistant mutants if patients are treated with a combination of two or more drugs with different targets. Interestingly, while quiescence prolongs the time until therapy reduces the number of cells to low levels or extinction, the therapy phase is irrelevant for the evolution of drug resistant mutants. If treatm