Angiotensin-converting enzyme 2 is a potential therapeutic target for EGFR-mutant lung adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• EGFR-mutant lung adenocarcinomas harbor a subpopulation of cells resistant to EGFR inhibitors due to epithelial-to-mesenchymal transition.
• Targeting this EGFR-independent, mesenchymal subpopulation is crucial for effective cancer treatment.

Purpose of the Study:

• To identify cell surface molecules expressed on EGFR-independent cancer cells as potential therapeutic targets.
• To evaluate the therapeutic potential of targeting angiotensin-converting enzyme 2 (ACE2) in EGFR-mutant lung adenocarcinoma.

Main Methods:

• Comparative analysis of ACE2 expression in EGFR-independent mesenchymal HCC827 sublines versus parental cells.
• Assessment of ACE2 expression in primary EGFR-mutant lung adenocarcinomas and normal lung tissues.
• Development and characterization of an anti-ACE2 mouse monoclonal antibody (H8R64) for cellular internalization.

Main Results:

• Mesenchymal EGFR-independent HCC827 cells showed significantly higher ACE2 expression than parental cells.
• ACE2 was expressed in most primary EGFR-mutant lung adenocarcinomas, with higher levels in cancer cells compared to normal lung epithelium.
• The developed anti-ACE2 antibody (H8R64) demonstrated internalization by ACE2-expressing cells.

Conclusions:

• ACE2 is a promising cell surface target for EGFR-independent EGFR-mutant lung adenocarcinoma.
• An antibody-drug conjugate utilizing a humanized anti-ACE2 antibody could offer a novel therapeutic strategy for this patient population.