Combined therapy with EGFR TKI and gambogic acid for overcoming resistance in EGFR‑T790M mutant lung cancer

Wang,Chengde; Wang,Wei; Wang,Chaoyang; Tang,Yijun; Tian,Hui

doi:10.3892/ol.2015.3599

Combined therapy with EGFR TKI and gambogic acid for overcoming resistance in EGFR‑T790M mutant lung cancer

Authors:
- Chengde Wang
- Wei Wang
- Chaoyang Wang
- Yijun Tang
- Hui Tian
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Affiliations: Department of Thoracic Surgery, Qi Lu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Thoracic Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
Published online on: August 12, 2015 https://doi.org/10.3892/ol.2015.3599
Pages: 2063-2066
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although patients with non‑small cell lung cancer (NSCLC) experience an initial response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, those individuals with activating mutations in EGFR develop resistance. Gambogic acid (GA), a polyprenylated xanthone, has strong antitumor activities. In the present study, the therapeutic efficacy of gefitinib with GA was evaluated in a gefitinib‑resistant NSCLC model. The NCI‑H1975 cell line with EGFR‑T790M mutation was subcutaneously injected into immunocompromised mice. The mice were randomly assigned to receive treatment with gefitinib, GA, gefitinib plus GA, or vehicle for 4 weeks, then all mice were sacrificed and their tumor tissues were subjected to caspase activity detection and western blot analysis. Gefitinib and GA alone slightly inhibited the tumor growth of NCI‑H1975. However, the combined treatment significantly enhanced their antitumor effects, without any marked adverse events. In addition, gefitinib plus GA enhanced the level of apoptosis in the tumor tissues. Western blot analysis also revealed that the combination treatment reduced the phosphorylation level of AKT, MEK1/2 and ERK1/2, while an increased expression ratio of Bax/Bcl‑2 was observed. In the current study, gefitinib in combination with GA resulted in antitumor growth in the EGFR‑T790M secondary mutation NCI‑H1975 tumor model due to an enhanced apoptotic effect. This novel therapeutic strategy may be a practical approach for the treatment of patients who show gefitinib resistance.

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