Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling.
Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling.
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DOI：
10.1126/scitranslmed.3002356
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发表时间：
2011-07-06
影响因子：
17.1
通讯作者：
Pao W
中科院分区：
文献类型：
--
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
表皮生长因子受体（EGFR）基因突变的非小细胞肺癌（NSCLC）对酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼敏感。不幸的是，所有接受这些药物治疗的患者都将获得耐药性，最常见的是由于EGFR（T790M）内的继发性突变。因为这两种药物都是针对野生型EGFR开发的，我们假设目前的给药方案没有针对突变型EGFR或预防耐药性进行优化。为了进一步研究这一点，我们开发了模拟人类肿瘤行为的同基因TKI敏感和TKI耐药细胞系对。我们确定，药物敏感和耐药EGFR突变体细胞表现出不同的生长动力学，与耐药细胞表现出较慢的增长。我们将这些数据整合到进化数学癌症模型中，这些模型具有来自临床数据集的约束。该模型预测了替代治疗策略，这些策略可以通过延迟耐药性的发展来延长TKI对EGFR突变型NSCLC的临床获益。
Non–small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.
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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
影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
在连续和脉冲给药策略期间对靶向抗癌疗法的抵抗力的演变。
影响因子：
4.3
作者：
Foo J;Michor F
通讯作者：
Michor F
DOI：
10.1158/1078-0432.ccr-10-2277
发表时间：
2011-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arcila ME;Oxnard GR;Nafa K;Riely GJ;Solomon SB;Zakowski MF;Kris MG;Pao W;Miller VA;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
39.2
作者：
GRALLA, RJ;CASPER, ES;GOLBEY, RB
通讯作者：
GOLBEY, RB