EGFR-directed antibodies promote HER2 ADC internalization and efficacy Journal Article
| Authors: | Gupta, A.; Michelini, F.; Shao, H.; Yeh, C.; Drago, J. Z.; Liu, D.; Rosiek, E.; Romin, Y.; Ghafourian, N.; Thyparambil, S.; Misale, S.; Park, W.; de Stanchina, E.; Janjigian, Y. Y.; Yaeger, R.; Li, B. T.; Chandarlapaty, S. |
| Article Title: | EGFR-directed antibodies promote HER2 ADC internalization and efficacy |
| Abstract: | Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor's conformation and context. We hypothesize that epidermal growth factor receptor (EGFR), a dimerization partner of HER2, can modulate HER2 trafficking through endocytic pathways and affect T-DXd uptake. We demonstrate that elevated EGFR expression levels can promote EGFR/HER2 heterodimer formation and suppress T-DXd internalization and efficacy. Knockdown of EGFR expression or pharmacologic stimulation of EGFR endocytosis with EGFR monoclonal antibodies restores T-DXd trafficking and antitumor activity in EGFR-overexpressing cancers in vivo. Our results reveal EGFR overexpression to be a potential mechanism of resistance to T-DXd, which can be overcome by combination therapy strategies targeting EGFR. © 2024 The Author(s) |
| Keywords: | immunohistochemistry; controlled study; protein expression; gene mutation; human cell; nonhuman; flow cytometry; glioma; colorectal cancer; mass spectrometry; biological marker; animal cell; mouse; breast cancer; epidermal growth factor receptor; epidermal growth factor receptor 2; animal experiment; animal model; antineoplastic activity; tumor xenograft; cetuximab; histology; irinotecan; panitumumab; immunoprecipitation; immunoblotting; pancreas adenocarcinoma; tumor growth; trastuzumab; doxycycline; endocytosis; head and neck squamous cell carcinoma; diagnostic test accuracy study; limit of detection; homodimerization; human; article; antibody drug conjugate; trastuzumab deruxtecan; adc internalization; egfr overexpression; her2-positive cancers; t-dxd resistance |
| Journal Title: | Cell Reports Medicine |
| Volume: | 5 |
| Issue: | 11 |
| ISSN: | 2666-3791 |
| Publisher: | Cell Press |
| Date Published: | 2024-11-19 |
| Start Page: | 101792 |
| Language: | English |
| DOI: | 10.1016/j.xcrm.2024.101792 |
| PUBMED: | 39437778 |
| PROVIDER: | scopus |
| PMCID: | PMC11604483 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Sarat Chandarlapaty -- Source: Scopus |
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