Targeting both wild-type EGFR and its drug-resistant mutants with erlotinib-aptamer conjugates

The epidermal growth factor receptor (EGFR) mutation is an actionable oncogenic driver in non-small-cell lung cancer (NSCLC). Although multiple generations of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been approved for the treatment of advanced NSCLC, acquired drug resistance after long-term administration challenges their therapeutic efficacy. In this study, using the first-generation agent erlotinib as a warhead for EGFR and an aptamer targeting insulin-like growth factor 2 receptor (IGF2R) as a recruiter for the lysosome-shuttling receptor, we develop a pan-EGFR lysosome-targeting chimera (LYTAC). A series of EGFR degraders with different linker lengths are generated, among which LY-dE#5 is the most effective degrader that directs EGFR to the lysosomal pathway for degradation. Importantly, LY-dE#5 drives not only the downregulation of the wild-type but also the mutants which include 19del, L858R/T790M, 19del/T790M/C797S, and L858R/T790M/C797S, exhibiting superior antitumor activity over Osimertinib. Further in vitro and in vivo studies demonstrate that LY-dE#5 effectively suppresses the growth of EGFR-driven cancer cells. These data indicate that the erlotinib-aptamer conjugate is an efficient pan-EGFR degrader that holds the translational potential for cancer treatment to overcome the common drug-resistance issues of EGFR-TKIs.