WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers
Mei-Hua Jin1, Ah-Rong Nam1, Ju-Hee Bang1
1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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.
Insights
Blocking PD-L1 and targeting WEE1 can overcome trastuzumab resistance in HER2-positive cancers. This strategy enhances trastuzumab efficacy by downregulating PD-L1 and impacting key signaling pathways, offering hope for resistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Trastuzumab is a key therapy for HER2-positive breast and gastric cancers.
- Significant unmet need exists due to trastuzumab resistance mechanisms.
- Understanding resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate mechanisms of trastuzumab resistance in HER2-positive cancers.
- To identify strategies to overcome trastuzumab resistance.
- To evaluate the role of PD-L1 and WEE1 in trastuzumab resistance.
Main Methods:
- Generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer lines.
- Analyzed PD-L1 expression in parental and HR cells.
- Investigated the effect of PD-L1 blockade and WEE1 inhibition (adavosertib) on trastuzumab efficacy.
- Assessed impacts on signaling pathways (NF-κB, BRCA1-CMTM6-PD-L1, HER2-CDCP-1-SRC) and immune markers.
Main Results:
- Trastuzumab-resistant cells exhibited higher PD-L1 expression.
- Blocking PD-L1 reversed trastuzumab resistance.
- Trastuzumab upregulated PD-L1 via NF-κB, but only induced DNA damage in parental cells.
- WEE1 inhibitor adavosertib downregulated PD-L1, enhancing trastuzumab efficacy by disrupting specific signaling axes.
- WEE1 inhibition reduced immune suppressive markers in vitro.
Conclusions:
- Co-targeting HER2 and WEE1 is a promising strategy to overcome trastuzumab resistance.
- This approach enhances trastuzumab efficacy in HER2-positive cancers.
- Further clinical development is warranted for HER2-positive cancer patients with resistance.
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