A Cyclized Bivalent Aptamer-Based Protein Degrader Targeting Receptor Tyrosine Kinases Overcomes Resistance to Inhibitors in Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment for nonsmall cell lung Cancer (NSCLC) with EGFR mutations. However, their clinical success is limited by the eventual development of acquired resistance in patients mainly induced by EGFR mutations and the activation of alternative signaling pathways (e.g., c-Met). Herein, we reported a "one stone, two birds" strategy to combat the drug resistance of NSCLC to EGFR-TKIs by constructing a cyclized bivalent aptamer-based proteolysis-targeting chimera, or PROTAC, termed AHPC-cb-Ap, which efficiently degraded c-Met and its interacting multiple tyrosine kinases, including EGFR. By simultaneously degrading c-Met and EGFR, AHPC-cb-Ap could restore the sensitivity of erlotinib-resistant NCI-H1975 cells (EGFR^T790M/L858R) to erlotinib, both in vitro and in vivo. In a preclinical NCI-H1975 tumor model pretreated with AHPC-cb-Ap, erlotinib achieved approximately 70% antitumor efficacy, comparable to that of the third-generation EGFR-TKI osimertinib. Taken together, our strategy of simultaneously degrading c-Met and EGFR, which underlie resistance to EGFR-TKIs, provides a comprehensive approach to combat the drug resistance of NSCLC.

PROTACs; aptamer; drug resistance; lung cancer; protein degradation.