Maolan Li 1,2 , Fatao Liu 2 , Fei Zhang 1,2 , Weiping Zhou 3 , Xiaoqing Jiang 4 , Yuan Yang 3 , Kai Qu 5 , Yueqi Wang 6 , Qiang Ma 1,2 , Ting Wang 2 , Lu Bai 2 , Zheng Wang 1,2 , Xiaoling Song 1,2 , Yidi Zhu 1,2 , Ruiyan Yuan 1,2 , Yuan Gao 1,2 , Yongchen Liu 1,2 , Yunpeng Jin 1,2 , Huaifeng Li 1,2 , Shanshan Xiang 1,2 , Yuanyuan Ye 1,2 , Yijian Zhang 2 , Lin Jiang 2 , Yunping Hu 2 , Yajuan Hao 2 , Wei Lu 1,2 , Shili Chen 2 , Jun Gu 1,2 , Jian Zhou 2 , Wei Gong 1,2 , Yong Zhang 1 , Xuefeng Wang 1,2 , Xiyong Liu 7 , Chang Liu 5 , Houbao Liu 6 , Yun Liu 8 , Yingbin Liu 1,2 Show Affiliations »
Abstract
OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. CONCLUSIONS: ERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. TRIAL REGISTRATION NUMBER: NCT02442414;Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2 /ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2 /ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2 /ERBB3 mutation. Ectopic expression of ERBB2 /ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2 /ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. CONCLUSIONS: ERBB2 /ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2 /ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. TRIAL REGISTRATION NUMBER: NCT02442414;Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Entities: Disease
Gene
Species
Keywords:
ERBB2/ERBB3; Programmed death-ligand 1(PD-L1); gallbladder carcinoma; whole-exome sequencing
Mesh： See more »
Substances： See more »
Year: 2018
PMID： 29954840 DOI： 10.1136/gutjnl-2018-316039
Source DB: PubMed Journal: Gut ISSN： 0017-5749 Impact factor: 23.059