Open Access

Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

  • Authors:
    • Chi Pan
    • Huijie Duan
    • Yinan Wu
    • Chunpeng Zhu
    • Chenghao Yi
    • Yin Duan
    • Demin Lu
    • Cheng Guo
    • Deqi Wu
    • Yanyan Wang
    • Xianhua Fu
    • Jing Xu
    • Yiding Chen
    • Meng Luo
    • Wei Tian
    • Tao Pan
    • Wenhong Xu
    • Suzhan Zhang
    • Jianjin Huang
  • View Affiliations

  • Published online on: July 27, 2020     https://doi.org/10.3892/ijo.2020.5103
  • Pages: 939-955
  • Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum‑based chemotherapy is the main treatment for advanced non‑small‑cell lung cancer (NSCLC), and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) have greatly improved the survival of patients with EGFR‑sensitive mutations. However, there is no standard therapy for treating patients who are EGFR‑TKI resistant. Combining EGFR‑TKIs and platinum‑based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR‑TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR‑TKI) and cisplatin (a main platinum‑based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co‑immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA‑PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA‑dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.
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October-2020
Volume 57 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Pan C, Duan H, Wu Y, Zhu C, Yi C, Duan Y, Lu D, Guo C, Wu D, Wang Y, Wang Y, et al: Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. Int J Oncol 57: 939-955, 2020
APA
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y. ... Huang, J. (2020). Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. International Journal of Oncology, 57, 939-955. https://doi.org/10.3892/ijo.2020.5103
MLA
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y., Lu, D., Guo, C., Wu, D., Wang, Y., Fu, X., Xu, J., Chen, Y., Luo, M., Tian, W., Pan, T., Xu, W., Zhang, S., Huang, J."Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC". International Journal of Oncology 57.4 (2020): 939-955.
Chicago
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y., Lu, D., Guo, C., Wu, D., Wang, Y., Fu, X., Xu, J., Chen, Y., Luo, M., Tian, W., Pan, T., Xu, W., Zhang, S., Huang, J."Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC". International Journal of Oncology 57, no. 4 (2020): 939-955. https://doi.org/10.3892/ijo.2020.5103