WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers.
Gastric Cancer
; 24(5): 1003-1020, 2021 09.
Article
em En
| MEDLINE
| ID: mdl-33723720
ABSTRACT
BACKGROUND:
To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance.METHODS:
In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773).RESULTS:
Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro.CONCLUSION:
Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.Palavras-chave
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
/
Neoplasias da Mama
Limite:
Female
/
Humans
Idioma:
En
Revista:
Gastric Cancer
Ano de publicação:
2021
Tipo de documento:
Article