Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding
The mechanisms underlying clinical T-DXd resistance have not been established. We now report on two mechanisms of resistance that converge on loss of target binding and propose combinations of distinct ADCs with shared payloads as a strategy to overcome resistance by enhancing intratumor delivery. See related commentary by O'Meara and Tarantino, p.195.
Authors
- Fresia Pareja (ORCID: https://orcid.org/0000-0003-3748-8049)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Joshua Z. Drago (ORCID: https://orcid.org/0000-0002-7245-1172)
- Joshua Lau (ORCID: https://orcid.org/0009-0007-0955-6258)
- Pedram Razavi (ORCID: https://orcid.org/0000-0003-4236-0576)
- Shanu Modi (ORCID: https://orcid.org/0000-0001-6427-7373)
- Sharanya Nag (ORCID: https://orcid.org/0009-0009-2517-9389)
- Avantika Gupta (ORCID: https://orcid.org/0000-0002-8170-6720)
- Jacqueline Bromberg (ORCID: https://orcid.org/0000-0002-7957-9339)
- Sarat Chandarlapaty (ORCID: https://orcid.org/0000-0003-4532-8053)
- Sukrit Singh (ORCID: https://orcid.org/0000-0003-1914-4955)
- Nicholas Mai (ORCID: https://orcid.org/0000-0002-1900-7945)
- Atif A Hashmi (ORCID: https://orcid.org/0000-0001-9999-871X)
- Wanyi Chen (ORCID: https://orcid.org/0000-0002-0876-4203)
- John D. Chodera (ORCID: https://orcid.org/0000-0003-0542-119X)
- Miriam M. Klar (ORCID: https://orcid.org/0000-0001-7609-5470)
- Bo Liu (ORCID: https://orcid.org/0000-0002-4511-6926)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0647
- Citations
- 6
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 6.27
Funders
- National Science Foundation
- Breast Cancer Research Foundation
- Damon Runyon Cancer Research Foundation
- Eli Lilly and Company
- AstraZeneca
- Memorial Sloan-Kettering Cancer Center
- Merck KGaA
- Parker Institute for Cancer Immunotherapy
- Cycle for Survival
- Entasis Therapeutics
- Relay Therapeutics
- XtalPi
- Daiichi-Sankyo
- National Institutes of Health
- EMD Serono
- National Cancer Institute
- Daiichi Sankyo Europe