Understanding the role of phenotypic switching in cancer drug resistance.
Understanding the role of phenotypic switching in cancer drug resistance.
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DOI：
10.1016/j.jtbi.2020.110162
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发表时间：
2020-04-07
影响因子：
2
通讯作者：
Foo J
中科院分区：
文献类型：
--
作者：
Gunnarsson EB;De S;Leder K;Foo J
癌症中获得性耐药性的出现是治疗成功的主要障碍。虽然研究传统上集中在耐药性的遗传来源，但最近的研究结果表明，癌细胞可以通过表观遗传修饰和其他非遗传机制获得瞬时耐药表型。尽管这些耐药表型最终会被单个细胞放弃，但它们可以暂时“拯救”肿瘤免于灭绝，并使更持久的耐药机制得以出现。这些观察结果引起了人们对表观遗传疗法用于长期肿瘤控制或根除的潜力的兴趣。在这项工作中，我们开发了一个数学模型来研究单细胞水平的表型转换如何影响癌症的耐药性演变。我们强调非遗传性耐药的独特特征，探索表观遗传药物的进化后果，并探索潜在的治疗策略。我们发现，即使是短期的表观遗传修饰和基因表达的随机波动，也可以在没有任何真正的耐药机制的情况下驱动长期耐药。我们还发现，一种稍微干扰耐药表型平均保留的表观遗传药物可以将保证的治疗失败转变为保证的成功。最后，我们发现，将表观遗传药物与抗癌药物相结合可以显着优于单药治疗，并且治疗结果受到药物测序的严重影响。
The emergence of acquired drug resistance in cancer represents a major barrier to treatment success. While research has traditionally focused on genetic sources of resistance, recent findings suggest that cancer cells can acquire transient resistant phenotypes via epigenetic modifications and other non-genetic mechanisms. Although these resistant phenotypes are eventually relinquished by individual cells, they can temporarily ’save’ the tumor from extinction and enable the emergence of more permanent resistance mechanisms. These observations have generated interest in the potential of epigenetic therapies for long-term tumor control or eradication. In this work, we develop a mathematical model to study how phenotypic switching at the single-cell level affects resistance evolution in cancer. We highlight unique features of non-genetic resistance, probe the evolutionary consequences of epigenetic drugs and explore potential therapeutic strategies. We find that even short-term epigenetic modifications and stochastic fluctuations in gene expression can drive long-term drug resistance in the absence of any bona fide resistance mechanisms. We also find that an epigenetic drug that slightly perturbs the average retention of the resistant phenotype can turn guaranteed treatment failure into guaranteed success. Lastly, we find that combining an epigenetic drug with an anti-cancer agent can significantly outperform monotherapy, and that treatment outcome is heavily affected by drug sequencing.
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影响因子：
17.1
作者：
Chmielecki J;Foo J;Oxnard GR;Hutchinson K;Ohashi K;Somwar R;Wang L;Amato KR;Arcila M;Sos ML;Socci ND;Viale A;de Stanchina E;Ginsberg MS;Thomas RK;Kris MG;Inoue A;Ladanyi M;Miller VA;Michor F;Pao W
通讯作者：
Pao W
在单细胞水平上表观遗传调节的动力学。
DOI：
10.1126/science.aab2956
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bintu L;Yong J;Antebi YE;McCue K;Kazuki Y;Uno N;Oshimura M;Elowitz MB
通讯作者：
Elowitz MB
影响因子：
4.7
作者：
Jolly MK;Kulkarni P;Weninger K;Orban J;Levine H
通讯作者：
Levine H
影响因子：
64.5
作者：
Leder K;Pitter K;LaPlant Q;Hambardzumyan D;Ross BD;Chan TA;Holland EC;Michor F
通讯作者：
Michor F
影响因子：
64.8
作者：
Chang, Hannah H.;Hemberg, Martin;Huang, Sui
通讯作者：
Huang, Sui