Highly Specific Cytokine Receptor‐Targeting Chimeras for Targeted Membrane Protein Degradation and Sensitization of Osimertinib in EGFR‐Mutated Non‐Small‐Cell Lung Cancer

Abstract

Abstract The ability of cytokine receptors to mediate the internalization of targets in lysosomes positions them as specific and effective effectors for protein degradation strategies. However, challenges remain, including the potential unintended activation of cell‐proliferation‐related cytokine receptors, as well as limitations in programmability and structural flexibility of protein degradators. In this work, a CXCR7‐targeting chimera (AP‐CRTAC) that functions as a CXCR7 inducer by covalently linking a membrane protein‐targeting aptamer with a mutant‐CXCL12 mimic peptide is developed. This peptide selectively binds to CXCR7 without activating CXCR4. The AP‐CRTAC, which incorporates various aptamer forms from DNA, RNA, or even bispecific aptamers, has shown significant efficacy in degrading one or more proteins or protein mutants on the cell surface. Moreover, the AP‐CRTAC constructed with a 2′ F‐pyrimidine‐modified RNA aptamer targeting EGFR effectively degrades various EGFR activating mutations. Notably, AP‐CRTAC enhances the sensitivity of the L858R/T790M/C797S triple mutant lung cancer cells, which are resistant to current EGFR‐targeted therapies, to the third‐generation EGFR inhibitor osimertinib in both in vitro and in vivo settings. This research introduces an engineered CXCR7 inducer with high specificity and programmability for the targeted degradation of cell surface proteins, while minimizing unwanted side effects.