Enhancement of chemosensitivity by WEE1 inhibition in EGFR-TKIs resistant non-small cell lung cancer
Autor: | Na Wang, Di Liu, Xiao Zhou, Wen Xu, Ziyang Cao, Bo Su, Xi Ding, Ge Lin, Chunyan Wu |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine Lung Neoplasms Cell Cycle Proteins Deoxycytidine 0302 clinical medicine Non-small cell lung cancer Carcinoma Non-Small-Cell Lung Crown Ethers Medicine Epidermal growth factor receptor RNA Small Interfering Aged 80 and over Gene knockdown biology Gefitinib General Medicine Middle Aged Protein-Tyrosine Kinases ErbB Receptors G2 Phase Cell Cycle Checkpoints Wee1 030220 oncology & carcinogenesis Female Tyrosine kinase medicine.drug EGFR Antineoplastic Agents RM1-950 03 medical and health sciences Cell Line Tumor Humans Chemotherapy WEE1 Lung cancer Aged Tyrosine kinase inhibitors Pharmacology Cisplatin business.industry medicine.disease Gemcitabine respiratory tract diseases 030104 developmental biology Drug Resistance Neoplasm Drug resistance Icotinib Quinazolines Cancer research biology.protein Therapeutics. Pharmacology business |
Zdroj: | Biomedicine & Pharmacotherapy, Vol 117, Iss, Pp-(2019) |
ISSN: | 0753-3322 |
Popis: | Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is the first-line treatment in non-resectable non-small lung cancer (NSCLC) with EGFR mutation. However, EGFR-TIKs resistance would inevitably develop within 9–14 months after treatment. And, chemotherapy is the main treatment for EGFR-TKIs resistant patients. WEE1 kinase, a G2/M checkpoint regulator, was recently considered as a putative biomarker for the platinum-based chemo-response. The aim of this study is to clarify the relationship between WEE1 kinase and chemosensitivity in EGFR-TKIs resistant NSCLC. WEE1 expression was tested in EGFR-TKIs resistant cell lines (H1299, PC9/G2) and patients’ specimens by western blot, qPCR and immunohistochemistry (IHC). In in vitro experiment, WEE1 expression was higher in EGFR-TKIs resistant than EGFR-TKIs sensitive cell lines and was gradually increased following cisplatin or gemcitabine treatment with the enrichment of G2/M cell cycle phase. And, for patients with acquired Icotinib/Gefitinib resistance, 58.4% (7/12) had increased WEE1 expression compared to its initial expression level. In order to explore the impact of WEE1 on chemo-response, WEE1 knockdown was conducted in EGFR-TKIs resistant H1299 and PC9/G2 cells. MTT and colony formation assay showed that the efficacy of cisplatin and gemcitabine was enhanced in the two cell lines after WEE1 knockdown. And, the IC50 value of cisplatin decreased from 8.64 μg/ml to 3.10 μg/ml or 2.38 μg/ml in H1299 and from 3.66 μg/ml to 0.97 μg/ml or 1.18 μg/ml in PC9/G2 after WEE1 knockdown with two specific shRNAs. This study revealed that WEE1 expression was increased after EGFR-TKIs resistance, and WEE1 knockdown could enhance chemosensitivity in EGFR-TKIs resistant NSCLC. It is suggested the combination of WEE1 inhibitor and chemotherapy might improve the clinical outcome of NSCLC patients with acquired EGFR-TKIs resistance. |
Databáze: | OpenAIRE |
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