Editors' ChoiceCancer

A bullet against gallbladder cancer

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Science Translational Medicine  18 Jul 2018:
Vol. 10, Issue 450, eaau7217
DOI: 10.1126/scitranslmed.aau7217

Abstract

ERBB2/3 mutations in gallbladder cancer are associated with immunosuppression and aggressive tumor development and can be targeted by ERBB2/3 inhibitors.

Patients diagnosed with gallbladder carcinoma (GBC) often have a poor prognosis, with an average 5-year survival rate of 5%. This is due to a limited understanding of the development of GBC, which translates to a lack of effective therapeutic strategies. Now, Li et al. have identified the role of the oncogene ERBB2 and ERBB3 (ERBB2/3) as a driver of aggressive GBC development in a subset of patients.

To identify genomic mutations that occur in GBC, the investigators performed whole-exome sequencing analysis of GBC samples from a cohort of 125 patients who had cholecystectomy (surgical removal of the gallbladder). They found that 7 to 8% of the patients had mutations in the ERBB2/3 oncogenes. Patients with ERBB2/3 mutations in GBC tended to have poorer prognosis after surgery than those without these mutations.

The researchers next investigated the associations between ERBB2/3 and aggressive GBC development. They observed that two human GBC cell lines overexpressing ERBB2/3 were more proliferative in vitro and when xenografted in vivo. In addition, programmed death ligand 1 (PD-L1) was up-regulated in GBC lines and patient cancer biopsies that highly expressed mutant ERBB2/3. The lower numbers of cytotoxic CD3+, CD4+, and CD8+ T cells identified in patient tumors expressing ERBB2/3 mutations suggested suppression of anticancer immunity. To propose a proof-of-concept combination therapy strategy against GBC, the researchers demonstrated in a mouse xenograft model that the ERBB2/3 inhibitor sapitinib potentiated the efficacy of the anti–PD-L1 antibody alezolizumab in suppressing tumor growth and promoting apoptosis.

A phase I clinical trial has been initiated to explore an ERBB2/3 inhibitor for GBC patients with the associated mutations to test whether ERBB2/3 could be an efficacious clinical target. The study also suggests ERBB2/3 as a potential biomarker for patients who may benefit from PD-L1 antibody and ERBB2/3 inhibitor combination therapy, although this needs to be clarified in a separate cohort. To evaluate whether this could be a general therapeutic strategy for GBC, further studies should address whether anti–PD-L1 immunotherapy could effectively target GBCs that do not harbor ERBB2/3 mutations.

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