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

This study develops a dual membrane receptor degradation platform called FolTAC-dual based on folate receptor alpha (FRα), effectively overcoming drug resistance by simultaneously targeting EGFR/HER2 and PD-L1/VISTA receptor pairs. Compared to traditional 'knob-into-hole' designs, the optimized 'string' configuration demonstrates enhanced binding affinity and degradation efficiency, offering new insights for combination cancer therapy.

 

Literature Overview
This article titled 'Dual membrane receptor degradation via folate receptor targeting chimera', published in Nature Communications, reviews cancer drug resistance mechanisms and degradation strategies targeting single or dual membrane receptors. The research validates anti-tumor and immune activation effects of the engineered FolTAC-dual platform through simultaneous EGFR/HER2 and PD-L1/VISTA degradation in vitro and in vivo models, establishing new directions for multi-target cancer therapy.

Background Knowledge
In cancer treatment, drug resistance remains a major challenge for targeted and immunotherapies. Resistance mechanisms often involve cross-talk signaling compensation between membrane receptors—for instance, HER2-targeted therapy resistance correlates with enhanced EGFR or HER3 signaling, while immune checkpoint resistance involves alternative receptor activation 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 range. FRα, with high-affinity folate binding, support for cell proliferation-related molecule synthesis, and overexpression in multiple cancers, serves as an ideal receptor for degradation platforms. The FRα-based FolTAC-dual system employs modular design for synchronized dual-receptor degradation, enhancing therapeutic specificity and efficacy to provide novel combination cancer strategies.

 

 

Research Methods and Experiments
The research team designed and optimized two configurations of the FolTAC platform: conventional 'knob-into-hole' and novel 'string' formats. 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 resistant cancer models.

Key Conclusions and Perspectives

• The 'string' configuration achieves approximately 85% higher binding affinity than 'knob-into-hole' in EGFR/HER2 dual degradation, effectively inhibiting tumor growth in resistant HER2+ breast cancer models
• PD-L1/VISTA dual-degrading FolTAC-dual significantly enhances T-cell activation in resistant MC38 mouse models, improving immune microenvironment and anti-tumor efficacy
• FRα overexpression across multiple cancers and its internalization mechanism effectively promote target protein entry into lysosomal degradation pathways, ensuring degradation efficiency
• Mechanistic studies reveal FolTAC-dual's enhanced dual-receptor degradation arises from synergistic binding effects, with optimized configurations reducing spatial hindrance and improving receptor binding stability
• In vivo pharmacokinetics demonstrate FolTAC-dual has approximately 6-day half-life, supporting clinical translation potential

Research Significance and Prospects
The FolTAC-dual platform establishes a novel paradigm for multi-target cancer therapy. Compared to traditional inhibition strategies, its receptor degradation approach effectively blocks resistance compensation signals and improves therapeutic durability. Future studies should expand to additional receptor pairs, optimize preclinical efficacy and safety profiles, and advance this platform for clinical translation in HER2+ and immune-resistant tumors.

 

 

Conclusion
The FolTAC-dual platform successfully enables dual membrane receptor degradation, effectively overcoming HER2-targeted and immune checkpoint therapy resistance. Through rational design, this platform improves binding affinity and degradation efficiency, offering an innovative tool for combination cancer therapy. It demonstrates potent anti-tumor activity in patient-derived organoids and mouse models with minimal toxicity to normal cells, showing strong clinical translation potential. Future research should focus on optimizing target combinations across cancer subtypes, improving pharmacokinetics, and conducting comprehensive safety evaluations to advance this platform toward clinical validation.

 

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