Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers.
Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers.
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DOI：
10.1371/journal.pone.0105724
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Haeno H
中科院分区：
文献类型：
--
作者：
Yamamoto KN;Hirota K;Takeda S;Haeno H
铂类药物和PARP抑制剂（“parpi”）被认为对DNA修复受损的brca相关癌症有效。这些药物导致复制分叉停滞和崩溃，并在缺乏修复机制的情况下有效地产生双链断裂，导致细胞周期停滞和诱导细胞死亡。然而，最近的研究表明，由于出现耐药性，这些化疗药物失败。在这项研究中，我们开发了一个BRCA相关癌症进展的随机模型，其中有四种癌症人群：(i)功能性BRCA， （ii）功能失调BRCA， （iii）功能性BRCA和生长优势，（iv）功能失调BRCA和生长优势。这四种癌症群体从一个具有正常修复功能的癌细胞扩展到细胞总数达到可检测的数量。我们导出了在检测时每个种群的概率和期望数的公式。此外，我们扩展了模型，考虑了治疗过程中肿瘤的动力学。该模型的结果经过验证，与brca相关癌症的临床和实验证据一致。基于该模型，我们研究了在治疗过程中，由于继发性突变，耐药性源自已有耐药群体或新生群体的情况。最后，我们发现铂类药物和parpi在以下情况下是有效的：(i) BRCA失活存在，（ii）癌症被早期诊断，（iii）肿瘤生长迅速。我们的研究结果表明，不同类型的癌症根据其生长和突变特征具有优先获得铂类药物和PARPis耐药的途径。
Platinum drugs and PARP inhibitors (“PARPis”) are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage. These four cancer populations expand from one cancer cell with normal repair function until the total cell number reaches a detectable amount. We derived formulas for the probability and expected numbers of each population at the time of detection. Furthermore, we extended the model to consider the tumor dynamics during treatment. Results from the model were validated and showed good agreement with clinical and experimental evidence in BRCA-associated cancers. Based on the model, we investigated conditions in which drug resistance during the treatment course originated from either a pre-existing drug-resistant population or a de novo population, due to secondary mutations. Finally, we found that platinum drugs and PARPis were effective if (i) BRCA inactivation is present, (ii) the cancer was diagnosed early, and (iii) tumor growth is rapid. Our results indicate that different types of cancers have a preferential way of acquiring resistance to platinum drugs and PARPis according to their growth and mutational characteristics.
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影响因子：
7.3
作者：
Ahmed, Ashour Ahmed;Etemadmoghadam, Dariush;Temple, Jillian;Lynch, Andy G.;Riad, Mohamed;Sharma, Raghwa;Stewart, Colin;Fereday, Sian;Caldas, Carlos;DeFazio, Anna;Bowtell, David;Brenton, James D.
通讯作者：
Brenton, James D.
影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
影响因子：
6.4
作者：
Buchholz, TA;Wu, XF;Brock, WA
通讯作者：
Brock, WA
影响因子：
6.2
作者：
Cass, I;Baldwin, RL;Karlan, BY
通讯作者：
Karlan, BY
影响因子：
3.7
作者：
Haeno H;Maruvka YE;Iwasa Y;Michor F
通讯作者：
Michor F