Targeting drug-tolerant persister cells: Let's bring on the TROPs!

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Non-small cell lung cancer (NSCLC) often develops resistance to Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs).
• A subpopulation of drug-tolerant persister (DTP) cells survives initial TKI treatment, leading to acquired resistance.
• Identifying vulnerabilities in these DTP cells is crucial for overcoming treatment resistance.

Purpose of the Study:

• To identify molecular targets that represent vulnerabilities in EGFR-TKI-resistant NSCLC cells.
• To evaluate the efficacy of targeting identified vulnerabilities to overcome TKI resistance.
• To support a novel therapeutic strategy for managing NSCLC treatment resistance.

Main Methods:

• Utilized drug-tolerant persister cell models derived from EGFR-mutant lung cancer.
• Performed molecular profiling to identify targets upregulated or essential in DTP cells.
• Tested the efficacy of anti-TROP2 antibody-drug conjugates (ADCs) against DTP cells in vitro and in vivo.

Main Results:

• Identified Tropomyosin receptor kinase B (TROP2) as a key vulnerability in EGFR-TKI DTP cells.
• Demonstrated that anti-TROP2 ADCs effectively target and eliminate this residual DTP population.
• Showed that targeting TROP2 can prevent the re-emergence of resistant clones.

Conclusions:

• TROP2 is a critical vulnerability in EGFR-TKI-tolerant persister lung cancer cells.
• Anti-TROP2 ADCs offer a promising therapeutic strategy to target residual disease and delay resistance.
• The "induce-target-kill" approach combining EGFR-TKI with anti-TROP2 therapy may improve clinical outcomes in NSCLC.