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
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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