CODE: Dual Membrane Receptor Degradation via Folate Receptor Targeting Chimera for Cancer Drug Resistance

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 developed an innovative dual membrane receptor degradation strategy leveraging Folate Receptor α (FRα) to address this issue. Folate Receptor α Targeting Chimeras (FolTAC-dual) are engineered degraders designed to selectively and simultaneously degrade distinct receptor pairs: (1) EGFR and HER2, and (2) PD-L1 and VISTA. Through modular optimization of binding configurations and linker geometries-including a novel “string” configuration- the string format exhibited around 85% lower KD compared to the conventional knob-into-hole design, indicating significantly enhanced EGFR binding affinity. Proof-of-concept studies demonstrated that EGFR and HER2 FolTAC-dual effectively counteracted resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenated immune responses in PD-L1 antibody-resistant syngeneic mouse models. These results highlight FolTAC-dual as a versatile platform to combat therapeutic resistance and enhance multi-receptor targeting strategies in cancer therapy.