Cabozantinib enhances the response of NSCLC cells with wild-type EGFR to erlotinib and pharmacodynamic modeling of their sequential combinations

doi:10.5246/jcps.2016.11.089

Abstract

Abstract:

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 (λ₀) and linear (λ₁) growth rates of H1299 cells were 0.0241 h^–1 and 360 cells·h^–1, respectively. The E_maxof 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.

Key words: Non-small cell lung cancer, Erlotinib, Cabozantinib, Sequential therapy, Pharmacodynamic modeling and simulation

CLC Number:

R943.5

Supporting:

Supplementary Figure S1. The standard curves used to count the cell numbers and the survival percentages of CAB monotherapy. The standard curves were used to calculate the cell numbers of H1299 (A-a) and A549 (A-b) cells. The survival percentages of CAB (1, 5 and 10 μM) of H1299 (B-a) and A549 (B-b) cells.

Supplementary Figure S12 The goodness-of-fit plots. The goodness-of-fit plots of the control group (a), ER group (b), CAB group (c) and the combination group (d). DV, Dependent variable (observed values); PRED, Predicted values; IPRED, Individual predicted values; CWRES, Conditional weighted residuals.

Supplementary Figure S3. The fitness of the natural growth of H1299 cells using Simeoni model (a), exponential model (b), and Logistic model (c). DV, Dependent variable (observed values); PRED, Predicted values.

Zhenzhen Mou, Siyuan Wang, Qinghong Su, Yin Yuan, Jingyun Li, Lijie Wang, Qingyu Yao, Shuangmin Ji, Wei Lu, Tianyan Zhou. Cabozantinib enhances the response of NSCLC cells with wild-type EGFR to erlotinib and pharmacodynamic modeling of their sequential combinations[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(11): 799-813.

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