In:
Gut, BMJ, Vol. 68, No. 6 ( 2019-06), p. 1024-1033
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0017-5749
,
1468-3288
DOI:
10.1136/gutjnl-2018-316039
DOI:
10.1136/gutjnl-2018-316039.supp1
DOI:
10.1136/gutjnl-2018-316039.supp2
DOI:
10.1136/gutjnl-2018-316039.supp3
DOI:
10.1136/gutjnl-2018-316039.supp4
DOI:
10.1136/gutjnl-2018-316039.supp5
DOI:
10.1136/gutjnl-2018-316039.supp6
DOI:
10.1136/gutjnl-2018-316039.supp7
DOI:
10.1136/gutjnl-2018-316039.supp8
DOI:
10.1136/gutjnl-2018-316039.supp12
DOI:
10.1136/gutjnl-2018-316039.supp10
DOI:
10.1136/gutjnl-2018-316039.supp11
DOI:
10.1136/gutjnl-2018-316039.supp13
DOI:
10.1136/gutjnl-2018-316039.supp9
Language:
English
Publisher:
BMJ
Publication Date:
2019
detail.hit.zdb_id:
1492637-4
