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A Path to Persistence after EGFR Inhibition.

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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.

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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.