Therapeutic implication of HER2 in advanced biliary tract cancer

Abstract

// Ah-Rong Nam 1, * , Ji-Won Kim 2, * , Yongjun Cha 1, 3 , Hyerim Ha 3 , Ji Eun Park 1 , Ju-Hee Bang 1 , Mei Hua Jin 1 , Kyung-Hun Lee 1, 3 , Tae-Yong Kim 1 , Sae-Won Han 1, 3 , Seock-Ah Im 1, 3 , Tae-You Kim 1, 3 , Do-Youn Oh 1, 3 , Yung-Jue Bang 1, 3 1 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea 2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea 3 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea * These authors contributed equally to this work Correspondence to: Do-Youn Oh, email: ohdoyoun@snu.ac.kr Keywords: HER2, biliary tract cancer, gallbladder cancer, trastuzumab, targeted therapy Received: February 18, 2016      Accepted: July 27, 2016      Published: August 09, 2016 ABSTRACT Currently, there is no validated therapeutic target for biliary tract cancer (BTC). This study aimed to investigate the pre-clinical and clinical implication of HER2 as a therapeutic target in BTC. We established two novel HER2-amplified BTC cell lines, SNU-2670 and SNU-2773, from gallbladder cancer patients. SNU-2670 and SNU-2773 cells were sensitive to trastuzumab, dacomitinib, and afatinib compared with nine HER2-negative BTC cell lines. Dacomitinib and afatinib led to G1 cell cycle arrest in SNU-2773 cells and apoptosis in SNU-2670 cells. Furthermore, dacomitinib, afatinib, and trastuzumab showed synergistic cytotoxicity when combined with some cytotoxic drugs including gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. In a SNU-2670 mouse xenograft model, trastuzumab demonstrated a good anti-tumor effect as a monotherapy and in combination with gemcitabine increasing apoptosis. In our clinical data, 13.0% of patients with advanced BTC were defined as HER2-positive. Of these, three patients completed HER2-targeted chemotherapy. Two of them demonstrated a partial response, and the other one showed stable disease for 18 weeks. In summary, these pre-clinical and clinical data suggest that HER2 could be a therapeutic target, and that a HER2-targeting strategy should be developed further in patients with HER2-positive advanced BTC.