Mei-Hua Jin1, Ah-Rong Nam1, Ju-Hee Bang1, Kyoung-Seok Oh1, Hye-Rim Seo1,2, Jae-Min Kim1,2, Jeesun Yoon3, Tae-Yong Kim1,3, Do-Youn Oh4,5,6. 1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. 2. Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Korea. 3. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. 4. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ohdoyoun@snu.ac.kr. 5. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. ohdoyoun@snu.ac.kr. 6. Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Korea. ohdoyoun@snu.ac.kr.
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.
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.
Authors: Xian Chen; Kwang-Huei Low; Angela Alexander; Yufeng Jiang; Cansu Karakas; Kenneth R Hess; Jason P W Carey; Tuyen N Bui; Smruthi Vijayaraghavan; Kurt W Evans; Min Yi; D Christian Ellis; Kwok-Leung Cheung; Ian O Ellis; Siqing Fu; Funda Meric-Bernstam; Kelly K Hunt; Khandan Keyomarsi Journal: Clin Cancer Res Date: 2018-09-04 Impact factor: 12.531
Authors: Bharat K R Chaganty; Songbo Qiu; Anneliese Gest; Yang Lu; Cristina Ivan; George A Calin; Louis M Weiner; Zhen Fan Journal: Cancer Lett Date: 2018-05-08 Impact factor: 8.679