WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers
Autor: | Kyoung Seok Oh, Tae Yong Kim, Ju Hee Bang, Mei Hua Jin, Jae Min Kim, Jeesun Yoon, Do Youn Oh, Ah Rong Nam, Hye Rim Seo |
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Rok vydání: | 2021 |
Předmět: |
Cancer Research
03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Trastuzumab Surgical oncology PD-L1 medicine skin and connective tissue diseases neoplasms biology business.industry Gastroenterology Cancer FOXP3 General Medicine medicine.disease Oncology Cell culture 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein 030211 gastroenterology & hepatology business medicine.drug |
Zdroj: | Gastric Cancer. 24:1003-1020 |
ISSN: | 1436-3305 1436-3291 |
Popis: | 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. 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). 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. 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. |
Databáze: | OpenAIRE |
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