siRNA-mediated inactivation of HER3 improves the antitumour activity and sensitivity of gefitinib in gastric cancer cells

// Heng-Heng Yuan 1, * , Ying-Nan Yang 2, * , Jian-Hua Zhou 1 , Yan-Jing Li 1 , Li-Ying Wang 3 , Jun-Wei Qin 4 , Tao Liu 5 , Zhen-Zhen Li 1 , Qing-Xin Zhou 1 , Xiao-Li Wei 1 , Ting-Ting Zhang 1 , Peng Huang 1 , Wen-Jie Zhang 1 , Lei Liu 1 , Xiao-Xue Du 1 and Yu Han 1 1 Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China 2 Department of Chest Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China 3 Department of Oncology, Chaoyang Central Hospital, Shenyang, Liaoning Province, China 4 Department of Oncology, Qingdao Municipal Hospital, Qingdao, Shandong Province, China 5 The Third Department of Oncology, Xinxiang Central Hospital, Xinxiang, Henan Province, China * These authors contributed equally to this work Correspondence to: Yu Han, email: hanyu_2017@126.com Keywords: HER3, siRNA, gefitinib, gastric cancer, PI3K/AKT Received: March 21, 2017      Accepted: April 17, 2017      Published: April 29, 2017 ABSTRACT The human EGFR family consists of four type-1 transmembrane tyrosine kinase receptors: HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER3 can dimerize with EGFR, HER2 and even c-Met and likely plays a central role in the response to EGFR-targeted therapy. Because HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. Here, we describe the stable suppression of HER3 mRNA and protein using siRNA. The inhibition of HER3 expression decreased cell proliferation, suppressed cell cycle progression, induced apoptosis and inhibited cell motility, migration, invasiveness, and soft agar growth. In addition, we found that gefitinib treatment increased the HER3 and HER2 mRNA levels. The administration of various concentrations of gefitinib to HER3-knockdown cells enhanced antitumour activity and sensitivity due to the downregulation of protein phosphorylation via PI3K/AKT and ERK signalling. Our results support the use of combined treatments targeting multiple EGFR receptors, particularly the use of HER3 inhibitors combined with EGFR inhibitors, such as gefitinib.