Dual membrane receptor degradation via folate receptor targeting chimera
Cancer drug resistance poses a significant challenge in oncology, often driven by intricate cross-talk among membrane-bound receptors that compromise mono-targeted therapies. We develop a dual membrane receptor degradation strategy leveraging Folate Receptor α (FRα) to address this issue. Folate Receptor α Targeting Chimeras-dual (FolTAC-dual) are engineered degraders designed to selectively and simultaneously degrade distinct receptor pairs: (1) EGFR/HER2 and (2) PD-L1/VISTA. Through modular optimization of modality configurations and geometries, we identify the "string" format as the most effective construct. Mechanistic studies demonstrate an ~85% increase in EGFR-binding affinity compared to the conventional knob-into-hole design, likely contributing to the improved efficiency of dual-target degradation. Proof-of-concept studies reveal that EGFR and HER2 FolTAC-dual effectively counteracts resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenates immune responses in PD-L1 antibody-resistant syngeneic mouse models. These findings establish FolTAC-dual as a promising dual-degradation platform for clinical translation.
Authors
- Ting Wu (ORCID: https://orcid.org/0000-0002-1806-3056)
- Wenyi Wei (ORCID: https://orcid.org/0000-0003-0512-3811)
- Dingpeng Zhang (ORCID: https://orcid.org/0000-0001-9652-0067)
- Jenny M. Hogstrom (ORCID: https://orcid.org/0000-0001-5932-0146)
- Taru E. Muranen (ORCID: https://orcid.org/0000-0003-4158-9002)
- Yihang Qi (ORCID: https://orcid.org/0000-0001-7589-0333)
- Hiroyuki Inuzuka
- Peiqiang Yan (ORCID: https://orcid.org/0009-0004-2618-225X)
- Zhen Wang (ORCID: https://orcid.org/0009-0008-5083-1853)
- Bolin Liu (ORCID: https://orcid.org/0000-0003-0150-8650)
- Zhixin Li (ORCID: https://orcid.org/0009-0000-6086-5733)
- Jingchao Wang (ORCID: https://orcid.org/0009-0001-9092-667X)
- Daoyuan Huang (ORCID: https://orcid.org/0000-0002-6680-7734)
- Tao Hou (ORCID: https://orcid.org/0000-0002-4836-7181)
- X. Shi
- Rui Jing
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Cornell University (US)
- Stanley Foundation (US)
- Methodist Hospital (US)
- Dana-Farber Cancer Institute (US)
- Massachusetts Institute of Technology (US)
- Louisiana State University Health Sciences Center New Orleans (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s41467-025-63882-5
- Citations
- 3
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- AstraZeneca
- National Institutes of Health