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

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.

• 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
• Journal: International journal of oncology (Int J Oncol) Vol. 57 Issue 4 Pg. 939-955 (10 2020) ISSN: 1791-2423 [Electronic] Greece
• PMID: 32945394 (Publication Type: Journal Article)

Chemical References

• KRAS protein, human
• EGFR protein, human
• ErbB Receptors
• DNA-Activated Protein Kinase
• Proto-Oncogene Proteins p21(ras)
• Cisplatin
• Gefitinib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (administration & dosage, pharmacology)
• DNA-Activated Protein Kinase (antagonists & inhibitors, metabolism)
• Drug Resistance, Neoplasm
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Gefitinib (administration & dosage, pharmacology)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Mutation
• Proto-Oncogene Proteins p21(ras) (metabolism)
• Xenograft Model Antitumor Assays