A Path to Persistence after EGFR Inhibition
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View abstract on PubMed
Summary
This summary is machine-generated.Drug-tolerant persister cells in EGFR-mutant lung cancer can cause relapse after targeted therapy. ASCL1 drives this persistence by promoting an epithelial-to-mesenchymal transition, offering potential new therapeutic targets.
Area Of Science
- Oncology
- Molecular Biology
- Genetics
Background
- Residual cancer cells, known as drug-tolerant persisters (DTPs), can lead to acquired drug resistance and tumor relapse after targeted therapies.
- In EGFR-mutant non-small cell lung cancer (NSCLC), DTPs are responsible for relapse despite initial response to tyrosine kinase inhibitors (TKIs).
- Understanding the phenotypic plasticity and in vivo mechanisms of DTPs is crucial, as current in vitro studies are limited.
Purpose Of The Study
- To investigate the mechanisms of DTP persistence in EGFR-mutant lung cancer following treatment with the TKI osimertinib.
- To identify key molecular drivers and transcriptional programs associated with DTPs in vivo.
Main Methods
- Utilized patient-derived xenograft models of EGFR-mutant lung cancer treated with osimertinib.
- Employed bulk and single-cell RNA sequencing to analyze DTPs at the time of maximal treatment response.
Main Results
- Identified a DTP transcriptional cluster mediated by the transcription factor ASCL1.
- ASCL1 overexpression was found to increase osimertinib tolerance in vitro and trigger an epithelial-to-mesenchymal transition (EMT) transcriptional program.
- ASCL1's ability to induce persistence was context-dependent, occurring only in epigenetically permissive cells.
Conclusions
- ASCL1 plays a significant role in mediating DTP heterogeneity and persistence in EGFR-mutant NSCLC treated with osimertinib.
- These findings highlight ASCL1 as a potential therapeutic target for overcoming drug resistance and preventing tumor relapse.
- The study provides insights into the context-dependent nature of DTP mechanisms, particularly in relation to epigenetic permissiveness.
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