Chk1 activation attenuates sensitivity of lapatinib in HER2-positive gastric cancer.

Authors:
Ming Bai
Ming Bai
Fourth Military Medical University
China
Na Song
Na Song
a Institute of Evolution and Marine Biodiversity
China
Dr. Xiaofang Che, MD, PhD
Dr. Xiaofang Che, MD, PhD
China Medical University
Shenyang, Liaoning | China
Xiaoxun Wang
Xiaoxun Wang
Anhui Key Laboratory of Chemo-Biosensing; Key Laboratory of Functional Molecular Solids
Xiujuan Qu
Xiujuan Qu
The First Hospital of China Medical University
Shenyang Shi | China
Yunpeng Liu
Yunpeng Liu
The First Hospital of China Medical University
China

Cell Biol Int 2018 Jul 14;42(7):781-793. Epub 2018 May 14.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China.

The ATM and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) pathway plays a pivotal role in DNA damage sensor and modulating homologous recombination. Recently, emerging evidence demonstrated that Chk1 phosphorylation was associated with chemotherapy and radiotherapy resistance. In this study, we explored the effect of ATR/Chk1 pathway on regulating lapatinib sensitivity in human epidermal growth factor receptor-2 (HER2)-positive gastric cancer cell lines. We selected two HER2-positive gastric cancer cell lines, and NCI-N87 cells exhibited higher sensitivity than MKN7 cells. Application of lapatinib inhibited phosphorylated HER2 and EGFR and the formation of epidermal growth factor receptor (EGFR)/HER2 complex in both cells. In NCI-N87 cells, lapatinib induced G1 arrest and reduced Chk1 phosphorylation through inhibiting the expression of DNA topoisomerase 2-binding protein 1 (TopBP1). While in MKN7 cells, no significant cell cycle transition was found and phosphorylated Chk1 was mildly upregulated. Inhibition of Chk1 phosphorylation enhanced the lapatinib sensitivity of MKN7 cells, which was shown by potentiated anti-proliferative effect, G1 arrest, downregulation of phosphorylated AKT and ERK along with aggravated DNA damage. In addition, increased Chk1 phosphorylation in NCI-N87 cells attenuated lapatinib-induced anti-proliferative effect and G1 arrest, and abrogated reduced phosphorylated AKT and ERK. Taken together, our study provides a novel mechanism for regulating lapatinib sensitivity in HER2 positive gastric cancer cells, suggesting a new strategy in clinical treatment.

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http://dx.doi.org/10.1002/cbin.10922DOI Listing

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July 2018
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