ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3
Eva A Ebbing1,2, Jan Paul Medema1,3, Helene Damhofer1
1Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
Abstract:
Receptor tyrosine kinases of the HER-family are involved in the development and progression of multiple epithelial tumors, and have consequently become widely used targets for new anti-cancer therapies. Trastuzumab, an antibody against HER2, has shown potent growth inhibitory effects on HER2 overexpressing tumors, including gastro-esophageal cancer, however, resistance to this therapy is inevitable. Unfortunately, a paucity of data on the cellular mechanisms of resistance to targeted therapeutic agents exists in esophageal adenocarcinoma. Using primary established HER2-overexpressing cultures and patient-derived xenograft models, we now reveal a novel resistance mechanism to trastuzumab in esophageal cancer: In response to trastuzumab, both HER3 and the metalloprotease ADAM10 are simultaneously upregulated. The proteolytic activity of the latter then releases the HER3 ligand heregulin from the cell surface to activate HER3 and confer resistance to trastuzumab by inducing compensatory growth factor receptor signaling. Blocking either HER3 or ADAM10 effectively reverts the acquired resistance to trastuzumab. Our data thus provide strategies to inhibit this signaling and circumvent resistance to trastuzumab.
Insights
Trastuzumab resistance in esophageal cancer involves increased HER3 and ADAM10. This mechanism releases heregulin, activating HER3 and bypassing HER2-targeted therapy. Blocking HER3 or ADAM10 can overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Receptor tyrosine kinases (RTKs) of the HER-family are crucial in epithelial tumor development.
- Trastuzumab, an anti-HER2 antibody, shows efficacy in HER2-overexpressing cancers like esophageal cancer.
- Resistance to targeted therapies like Trastuzumab is a significant clinical challenge, particularly in esophageal adenocarcinoma.
Purpose of the Study:
- To elucidate novel cellular mechanisms of Trastuzumab resistance in esophageal cancer.
- To identify potential therapeutic strategies to overcome Trastuzumab resistance.
Main Methods:
- Utilized primary HER2-overexpressing esophageal cancer cell cultures.
- Employed patient-derived xenograft (PDX) models of esophageal cancer.
- Investigated the roles of HER3 and ADAM10 in response to Trastuzumab treatment.
Main Results:
- Trastuzumab treatment led to simultaneous upregulation of HER3 and ADAM10 in HER2-overexpressing esophageal cancer models.
- ADAM10 activity released the HER3 ligand, heregulin, from the cell surface.
- This process activated compensatory HER3 signaling, conferring resistance to Trastuzumab.
- Inhibition of either HER3 or ADAM10 effectively reversed Trastuzumab resistance.
Conclusions:
- A novel resistance mechanism to Trastuzumab in esophageal cancer involves HER3 and ADAM10 activation.
- Targeting the HER3-ADAM10 signaling axis presents a viable strategy to circumvent Trastuzumab resistance.
- These findings offer potential therapeutic avenues for improving outcomes in esophageal adenocarcinoma patients.
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