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

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Epidermal growth factor receptor (EGFR) mutations drive non-small-cell lung cancer (NSCLC).
• Acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) limits treatment efficacy in advanced NSCLC.
• Targeting EGFR degradation offers a strategy to overcome resistance.

Purpose of the Study:

• To develop a novel pan-EGFR degrader using a lysosome-targeting chimera (LYTAC) approach.
• To evaluate the efficacy of the LYTAC in degrading wild-type and resistant EGFR mutants.
• To assess the therapeutic potential of the LYTAC in EGFR-driven cancers.

Main Methods:

• Conjugation of erlotinib (EGFR inhibitor) with an IGF2R-targeting aptamer to create a LYTAC.
• Generation and optimization of EGFR degraders with varying linker lengths.
• In vitro and in vivo assessment of EGFR degradation and antitumor activity.

Main Results:

• LYTAC LY-dE#5 demonstrated efficient degradation of wild-type EGFR and clinically relevant mutants (19del, L858R/T790M, 19del/T790M/C797S, L858R/T790M/C797S).
• LY-dE#5 exhibited superior antitumor activity compared to Osimertinib.
• Effective suppression of EGFR-driven cancer cell growth was observed in vitro and in vivo.

Conclusions:

• The developed erlotinib-aptamer conjugate (LYTAC) is an effective pan-EGFR degrader.
• This LYTAC approach successfully targets EGFR for lysosomal degradation, overcoming TKI resistance.
• The LYTAC demonstrates translational potential for treating NSCLC and other EGFR-driven malignancies.