中文摘要：

单独使用表皮生长因子受体类酪氨酸激酶抑制剂（EGFR-TKI）对EGFR野生型非小细胞肺癌（NSCLC）进行治疗,其药效不显著。本研究目的是对埃罗替尼（Erlotinib,ER）与卡博替尼（Cabozantinib,CAB）在EGFR野生型NSCLC细胞中的联合效应进行初步探讨,并通过建模与仿真（Modeling＆Simulation）对给药方案进行一定程度的优化。因此,本研究考察了ER与CAB联合给药对H1299和A549细胞活性、克隆、凋亡、迁移以及生长动力学的影响,并在体外建立药效模型（Pharmacodynamic model,PD model）对H1299细胞生长动力学进行描述,同时采用仿真方法对两药序贯联合方案进行优化。结果显示,CAB增强了H1299和A549细胞对ER的敏感性,所建模型对实验数据进行了较好的拟合,并通过建模得到了一系列重要参数。其中,H1299细胞指数生长速率（λ_0）与线性生长速率（λ_1）分别为0.0241 h~（–1）和360 cells？h~（–1）;ER与CAB的E_（max）分别为0.0091 h~（–1）和0.0085 h~（–1）,而两者EC50分别为0.812μM和1.16μM;模型估算协同指数φ为1.37（95%置信区间为1.24–1.50）,该值进一步验证了实验观测的ER与CAB间的协同效应;ER与CAB联合给药方案在H1299细胞中得到了进一步优化。总之,本研究从实验和建模两个方面验证了在EGFR野生型NSCLC细胞中ER与CAB间的协同抗肿瘤作用,以及证实了ER与CAB序贯治疗在EGFR野生型NSCLC细胞中的潜力,这为体内临床前及临床研究提供了参考。

英文摘要：

The epidermal growth factor receptor（EGFR）—tyrosine kinase inhibitors（TKIs） monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers（NSCLCs）. In the present study, we aimed to investigate the combined effect of erlotinib（ER） and cabozantinib（CAB） on NSCLC cell lines harboring wild-type EGFR and to optimize the dosage regimens using pharmacodynamic（PD） modeling and simulation. Therefore, we examined the combined effect of ER and CAB on cell viability, cloning, apoptosis induction, migration and growth dynamics in H1299 and A549 cells. PD modeling and simulation were also performed to quantitatively describe the H1299 cells growth dynamics and to optimize the dosage regimens as well. Our results showed that CAB effectively enhanced the sensitivity of both cell lines to ER. The PD models fitted the data well, and some important parameters were obtained. The exponential（λ_0） and linear（λ_1） growth rates of H1299 cells were 0.0241 h~（–1） and 360 cells？h~（–1）, respectively. The Emax of ER and CAB was 0.0091 h~（–1） and 0.0085 h~（–1）, and the EC50 was 0.812 μM and 1.16 μM, respectively. The synergistic effect observed in the experiments was further confirmed by the estimated combination index φ（1.37）,（95% confidence interval： 1.24–1.50）, obtained from PD modeling. Furthermore, the dosage regimens were optimized using simulations. In summary, both the experimental and modeling results demonstrated the synergistic interaction between ER and CAB in NSCLCs without EGFR mutations. Sequential combinations of ER and CAB provided an option for the therapy of the NSCLCs with wild-type EGFR, which would provide some references for preclinical study and translational research as well.