EGFR-directed antibodies promote HER2 ADC internalization and efficacy.

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.
Competing Interests: Declaration of interests F.M. is employed by AstraZeneca and reports stock and other ownership interests from AstraZeneca. J.Z.D. reports research funding from AstraZeneca and consulting fees from AstraZeneca, Genagon, AmMax Bio, NuProbe, and Launchpad Therapeutics. S.T. and N.G. are employed by mProbe and report research funding, stock, and other ownership interests from mProbe. S.M. reports grants from Boehringer Ingelheim and Daiichi Sankyo and serves on the scientific advisory board of Bionseek. Y.Y.J. acknowledges research funding from the National Cancer Institute, Department of Defense, Cycle for Survival, Fred’s Team, Inspirna, AstraZeneca, Arcus Biosciences, Bayer, Genentech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck, and Transcenta. She has served on advisory boards and/or done consulting for AbbVie, AmerisourceBergen, AskGene Pharma, Inc., Arcus Biosciences, Astellas, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi Sanyko, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, Inc., Imedex, Imugene, Inspirna, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Pfizer, Seagen, Silverback Therapeutics, and Zymeworks, Inc., as well as Clinical Care Options, HMP Education, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, and Research to Practice. She also holds stock options in Inspirna. W.P. acknowledges research funding from the National Cancer Institute, Break Through Cancer, Parker Institute for Cancer Immunotherapy (PICI), Society for Immunotherapy of Cancer, The Society of MSK, Merck, Astellas, Miracogen, Amgen, and Revolution Medicines. He has served on advisory boards and/or done consulting for Astellas, EXACT Therapeutics, and Innovent Biologics. He has received honoraria for continuing medical education for American Physician Institute and Integrity. R.Y. has served as an advisor for Array BioPharma/Pfizer, Mirati Therapeutics, and Amgen; received a speaker’s honorarium from Zai Lab; and has received research support to her institution from Array BioPharma/Pfizer, Boehringer Ingelheim, Boundless Bio, Mirati Therapeutics, and Daiichi Sankyo. B.T.L. reports grants and other support from Amgen and grants from the NIH during the conduct of the study; grants and personal fees from Hengrui USA; grants and other support from Genentech Roche, Lilly, AstraZeneca, and Daiichi Sankyo; nonfinancial support and other support from Resolution Bioscience; grants and nonfinancial support from MORE Health; nonfinancial support from Jiangsu Hengrui Medicine; personal fees from Boehringer Ingelheim; grants from the NIH outside the submitted work; and a patent for US62/685,057 issued, a patent for US62/514,661 issued, royalties from Karger Publishers, and licensing with Shanghai Jiao Tong University Press. S.C. has received personal consulting fees from Novartis, AstraZeneca, Nuvalent, Genesis Therapeutics, eFFECTOR Therapeutics, SAGA Diagnostics, Prelude Therapeutics, and Casdin Capital. S.C. has research funding from AstraZeneca and Daiichi Sankyo.
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