Nature Communications | FolTAC-dual platform overcomes cancer drug resistance through dual membrane receptor degradation

This study developed a dual-membrane receptor degradation platform called FolTAC-dual based on folate receptor alpha (FRα), which effectively overcomes drug resistance by simultaneously targeting EGFR/HER2 and PD-L1/VISTA receptor pairs. The optimized 'string' configuration demonstrates higher binding affinity and degradation efficiency compared to traditional 'knob-into-hole' designs, providing novel insights for combined cancer therapies.

 

Literature Overview
The article 'Dual membrane receptor degradation via folate receptor targeting chimera' published in Nature Communications reviews cancer drug resistance mechanisms and degradation strategies for single/dual membrane receptors. The research validates the FolTAC-dual platform through in vitro and in vivo models, demonstrating its anti-tumor and immune-activation effects while offering new directions for multi-target cancer therapies.

Background Knowledge
Drug resistance remains a major challenge in cancer treatment, particularly for targeted and immunotherapies. Resistance mechanisms often involve crosstalk signaling compensation between membrane receptors—for instance, HER2-targeted therapy resistance correlates with enhanced EGFR/HER3 signaling, while immunotherapy resistance involves activation of alternative checkpoints like VISTA. Although bispecific antibodies can block dual pathways, they remain limited by resistance mechanisms. Emerging membrane protein degradation technologies like LYTAC show promise but face challenges in multi-target adaptability and receptor exploration. FRα, with high-affinity folate binding, roles in cell proliferation-related molecule synthesis, and overexpression in multiple cancers, serves as an ideal degradation platform receptor. The FRα-based FolTAC-dual system employs modular design for synchronized dual-receptor degradation, enhancing therapeutic specificity and efficacy for combined cancer treatments.

 

 

Research Methods and Experiments
The team designed and optimized two configurations of the FolTAC platform: traditional 'knob-into-hole' and novel 'string' configurations. Degradation efficiency against EGFR, HER2, PD-L1, and VISTA was evaluated through flow cytometry, Western blot, and competitive binding assays. Further validation included pharmacokinetic analysis, cell co-culture systems, and xenograft models to assess anti-tumor activity and immune activation in drug-resistant cancer models.

Key Conclusions and Perspectives

• The 'string' configuration achieved ~85% higher binding affinity in EGFR/HER2 dual degradation compared to 'knob-into-hole', effectively suppressing tumor growth in drug-resistant HER2+ breast cancer models
• PD-L1/VISTA dual-degrading FolTAC-dual significantly enhanced T cell activation in drug-resistant MC38 mouse models, improved the tumor immune microenvironment, and boosted anti-tumor efficacy
• FRα overexpression across multiple cancers combined with its efficient lysosomal degradation pathway internalization mechanism ensures robust target degradation efficiency
• Mechanistic studies reveal FolTAC-dual's enhanced dual-receptor degradation arises from synergistic binding effects, with optimized configurations minimizing spatial hindrance and improving receptor binding stability
• In vivo pharmacokinetics demonstrate a ~6-day half-life for FolTAC-dual, supporting its clinical translational potential

Research Significance and Prospects
The FolTAC-dual platform establishes a new paradigm for multi-target cancer therapy. Compared to traditional inhibition strategies, its receptor degradation approach effectively blocks resistance compensatory signaling and improves treatment durability. Future research should expand to additional receptor pairs, optimize preclinical efficacy/safety profiles, and advance platform translation for HER2+ and immune-resistant tumor applications.

 

 

Conclusion
The FolTAC-dual platform successfully achieves dual membrane receptor degradation, effectively overcoming HER2-targeted and immune checkpoint therapy resistance. Through rational design, it enhances binding affinity and degradation efficiency, providing an innovative tool for combined cancer therapy. Demonstrating potent anti-tumor activity in patient-derived organoids and mouse models with minimal cytotoxicity to normal cells, the platform shows strong translational potential. Future research should focus on optimizing target combinations across cancer subtypes, improving pharmacokinetics, and conducting safety assessments to advance clinical validation.

 

Zhen Wang, Zhixin Li, Jenny Högström, Dingpeng Zhang, and Wenyi Wei. Dual membrane receptor degradation via folate receptor targeting chimera. Nature Communications.