A comparison of mutation and amplification-driven resistance mechanisms and their impacts on tumor recurrence
A comparison of mutation and amplification-driven resistance mechanisms and their impacts on tumor recurrence
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突变和扩增驱动的耐药机制的比较及其对肿瘤复发的影响
DOI：
10.1007/s00285-023-01992-8
复制
发表时间：
2023
影响因子：
1.9
通讯作者：
Foo, Jasmine
中科院分区：
文献类型：
--
作者：
Li, Aaron;Kibby, Danika;Foo, Jasmine
由耐药性演变驱动的肿瘤复发是癌症治疗成功的主要障碍。肿瘤耐药性通常是由遗传改变引起的，如点突变，这是指单个基因组碱基对的修饰，或基因扩增，这是指含有基因的DNA区域的复制。这些机制通常赋予不同程度的阻力，并且它们往往以截然不同的频率发生。在这里，我们调查肿瘤复发动力学对这些耐药机制的依赖性，使用随机多类型分支过程模型。我们推导出肿瘤消退概率和肿瘤复发时间的确定性估计，肿瘤复发时间定义为最初对药物敏感的肿瘤在产生耐药性后超过其原始大小的时间。对于放大驱动和突变驱动的电阻模型，我们证明了关于随机递归时间收敛到其平均值的大数定律结果。此外，我们证明了充分和必要条件下的基因扩增模型的肿瘤逃脱灭绝，讨论生物学相关参数下的行为，并比较复发时间和肿瘤的组成突变和扩增模型分析和模拟。在比较这些机制中，我们发现由扩增与突变驱动的复发时间之间的比率线性地取决于获得与突变事件相同程度的抗性所需的扩增事件的数量，并且我们发现扩增和突变事件的相对频率在确定复发对于任何特定系统更快的机制中起着关键作用。在扩增驱动的耐药模型中，我们还观察到增加药物浓度导致肿瘤负荷的更强的初始降低，但最终复发的肿瘤群体异质性较低，更具侵袭性，并且具有更高水平的耐药性。
Tumor recurrence, driven by the evolution of drug resistance is a major barrier to therapeutic success in cancer. Tumor drug resistance is often caused by genetic alterations such as point mutation, which refers to the modification of a single genomic base pair, or gene amplification, which refers to the duplication of a region of DNA that contains a gene. These mechanisms typically confer varying degrees of resistance, and they tend to occur at vastly different frequencies. Here we investigate the dependence of tumor recurrence dynamics on these mechanisms of resistance, using stochastic multi-type branching process models. We derive tumor extinction probabilities and deterministic estimates for the tumor recurrence time, defined as the time when an initially drug sensitive tumor surpasses its original size after developing resistance. For models of amplification-driven and mutation-driven resistance, we prove law of large numbers results regarding the convergence of the stochastic recurrence times to their mean. Additionally, we prove sufficient and necessary conditions for a tumor to escape extinction under the gene amplification model, discuss behavior under biologically relevant parameters, and compare the recurrence time and tumor composition in the mutation and amplification models both analytically and using simulations. In comparing these mechanisms, we find that the ratio between recurrence times driven by amplification versus mutation depends linearly on the number of amplification events required to acquire the same degree of resistance as a mutation event, and we find that the relative frequency of amplification and mutation events plays a key role in determining the mechanism under which recurrence is more rapid for any specific system. In the amplification-driven resistance model, we also observe that increasing drug concentration leads to a stronger initial reduction in tumor burden, but that the eventual recurrent tumor population is less heterogeneous, more aggressive and harbors higher levels of drug-resistance.
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DOI：
10.3934/mbe.2010.7.905
发表时间：
2010-10
期刊：
Mathematical biosciences and engineering : MBE
影响因子：
--
作者：
Tomasetti C;Levy D
通讯作者：
Levy D
DOI：
10.1073/pnas.86.23.9441
发表时间：
1989-12-01
影响因子：
11.1
作者：
TLSTY, TD;MARGOLIN, BH;LUM, K
通讯作者：
LUM, K
可数无穷多类型分支过程的灭绝概率
影响因子：
1.2
作者：
S. Hautphenne;G. Latouche;G. Nguyen
通讯作者：
G. Nguyen
一维连续时间马尔可夫分支过程
DOI：
--
发表时间：
1972
期刊：
影响因子：
--
作者：
K. Athreya;P. Ney
通讯作者：
P. Ney
癌症复发时间偏差较大
影响因子：
1.4
作者：
Pranav Hanagal;K. Leder;Zicheng Wang
通讯作者：
Zicheng Wang