EGFR-directed antibodies promote HER2 ADC internalization and efficacy
Avantika Gupta, Flavia Michelini, Hong Shao, Celine Yeh, Joshua Z. Drago, Dazhi Liu, Eric Rosiek, Yevgeniy Romin, Negin Ghafourian, Sheeno Thyparambil, Sandra Misale, Wungki Park, Elisa de Stanchina, Yelena Y. Janjigian, Rona Yaeger, Bob T. Li, Sarat Chandarlapaty
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. • EGFR expression mediates resistance to the HER2 antibody drug conjugate (ADC) T-DXd • Overexpressed EGFR reduces HER2 homodimerization and HER2/ADC internalization • EGFR monoclonal antibodies (mAbs) restore HER2/ADC trafficking • Addition of EGFR mAbs enhances T-DXd efficacy in multiple cancer types Gupta et al. demonstrate that high EGFR expression mediates resistance to HER2 antibody drug conjugates (ADCs) including trastuzumab deruxtecan (T-DXd) by limiting HER2/ADC internalization. The addition of EGFR monoclonal antibodies enhances the antitumor activity of T-DXd in preclinical models of various tumor types, including KRAS- mutant tumors.