Targeting EGFR degradation by autophagosome degraders

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are standard treatments for non-small cell lung cancer (NSCLC).
• Acquired resistance to EGFR inhibitors, driven by new mutations, limits their clinical efficacy.
• Proteolysis targeting chimeras (PROTACs) show promise for degrading resistant EGFR, but new degraders are needed.

Purpose of the Study:

• To design and synthesize novel autophagosome-tethering compounds (ATTECs) for EGFR degradation.
• To evaluate the efficacy of EGFR-ATTECs in degrading EGFR and inhibiting NSCLC cell growth.
• To explore the therapeutic potential of EGFR-ATTECs in overcoming drug resistance.

Main Methods:

• Design and synthesis of a series of EGFR-ATTECs.
• In vitro biological evaluation, including EGFR degradation assays (DC50, Dmax) and cell viability assays.
• Mechanistic studies to elucidate the degradation pathway (lysosomal).
• In vivo studies to assess anti-tumor activity and degradation efficiency.

Main Results:

• Synthesized EGFR-ATTECs demonstrated the ability to degrade EGFR in NSCLC cells.
• Compound 12c showed potent EGFR degradation (DC50 = 0.98 μM, Dmax = 81%) in HCC827 cells.
• Degradation primarily occurred via the lysosomal pathway.
• Compound 12c exhibited promising inhibitory activity and degradation efficiency in vivo.

Conclusions:

• EGFR-ATTECs represent a new class of EGFR degraders with potential clinical applications.
• This strategy offers a novel therapeutic approach to combat drug resistance in EGFR-mutated NSCLC.
• Further development of EGFR-ATTECs could provide an expandable tool for targeting resistant mutations.