Dual membrane receptor degradation via folate receptor targeting chimera

Authors

Zhen Wang, Harvard University, Boston, MA
Zhixin Li, Dana-Farber Cancer Institute, Boston, MA
Jenny Högström, Harvard University, Boston, MA
Hiroyuki Inuzuka, Harvard University, Boston, MA
Rui Jing, Houston Methodist Cancer Center/Weill Cornell Medicine, Houston, TX
Peiqiang Yan, Harvard University, Boston, MA
Tao Hou, Harvard University, Boston, MA
Yihang Qi, Harvard University, Boston, MA
Daoyuan Huang, Harvard University, Boston, MA
Jingchao Wang, Harvard University, Boston, MA
Ting Wu, Boston Children's Hospital, Boston, MA
Xiaoying Shi, Brigham and Women's Hospital, Boston, MA
Bolin Liu, LSU Health Sciences Center – New OrleansFollow
Taru Muranen, Harvard University, Boston, MA
Dingpeng Zhang, Harvard University, Boston, MA
Wenyi Wei, Harvard University, Boston, MA

Document Type

Article

Publication Date

10-2-2025

Publication Title

Nature Communications

Abstract

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.

PubMed ID

41038820

Volume

16

Issue

1

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Wang, Zhen; Li, Zhixin; Högström, Jenny; Inuzuka, Hiroyuki; Jing, Rui; Yan, Peiqiang; Hou, Tao; Qi, Yihang; Huang, Daoyuan; Wang, Jingchao; Wu, Ting; Shi, Xiaoying; Liu, Bolin; Muranen, Taru; Zhang, Dingpeng; and Wei, Wenyi, "Dual membrane receptor degradation via folate receptor targeting chimera" (2025). School of Medicine Faculty Publications. 4199.
https://digitalscholar.lsuhsc.edu/som_facpubs/4199
10.1038/s41467-025-63882-5