J Cancer 2020; 11(2):334-344. doi:10.7150/jca.32989 This issue

Research Paper

SFI Enhances Therapeutic Efficiency of Gefitinib: An Insight into Reversal of Resistance to Targeted Therapy in Non-small Cell Lung Cancer Cells

Zhenzhen Pan1*, Kai Wang1*, Qiufang Chen2, Xiulan Zheng1, Zhengyu Song1, Xuansheng Ding1✉

1. China Pharmaceutical University, School of Basic Medicine and Clinical Pharmacy, Nanjing, 211198, China
2. Xiamen Maternity and Child Health Care Hospital, Xiamen, 361000, China
*Both authors contributed equally to this work.

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Citation:
Pan Z, Wang K, Chen Q, Zheng X, Song Z, Ding X. SFI Enhances Therapeutic Efficiency of Gefitinib: An Insight into Reversal of Resistance to Targeted Therapy in Non-small Cell Lung Cancer Cells. J Cancer 2020; 11(2):334-344. doi:10.7150/jca.32989. Available from https://www.jcancer.org/v11p0334.htm

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Abstract

Background: The clinical application of EGFR tyrosine kinase inhibitors is always accompanied by inevitable drug resistance. However, the mechanism remains elusive. In the present study, we investigate the involvement of MAPK/SREBP1 pathway in NSCLC gefitinib resistance and evaluate the synergistic effects of shenqi fuzheng injection (SFI) and gefitinib on NSCLC cells.

Methods: To investigate the MAPK/SREBP1 pathway involved in gefitinib resistance, Western blotting was used to examine p-MEK, p-ERK and SREBP1 expression in PC-9 and PC-9/GR cells, MTT was used on cell proliferation, wound healing assay was used on cell migration. To detect the cooperative effects of SFI and gefitinib, clonogenic assay was used on cell proliferation. Apoptosis assay was analyzed by flow cytometry. Immunofluorescence was used to detect gefitinib binding to EGFR. Western blotting was used to detect whether SFI regulate the resistance to gefitinib via the suppression of MAPK/SREBP1 pathway.

Results: Our results showed that MAPK/SREBP1 pathway mediated resistance to gefitinib in NSCLC cells. MAPK pathway was found to directly target SREBP1 and inhibition of SREBP1 increased gefitinib sensitivity. In addition, SFI showed cooperative anti-proliferation and pro-apoptosis impacts on gefitinib resistant cells via down-regulating MAPK/SREBP1 pathway. Moreover, the combination of SFI and gefitinib enhanced gefitinib binding to EGFR resulting in the restoration of sensitivity to gefitinib.

Conclusions: Taken together, MAPK/SREBP1 pathway could be regarded as the potential treatment target for overcoming resistance to EGFR-TKIs in NSCLC and adjuvant therapy of SFI could be a potential therapeutic strategy for gefitinib resistant treatment.

Keywords: non-small cell lung cancer, EGFR-TKI, drug resistance, SREBP1, shenqi fuzheng injection