APOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer
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View abstract on PubMed
Summary
This summary is machine-generated.APOBEC mutagenesis fuels cancer evolution and therapy resistance by promoting survival of drug-tolerant persister cells. Targeting APOBEC3 and ΔNp63 may offer new therapeutic strategies for lung cancer.
Area Of Science
- Oncology
- Molecular Biology
- Genetics
Background
- APOBEC mutagenesis is a significant driver of cancer genetic heterogeneity and is linked to poor prognosis.
- The precise mechanisms by which APOBEC contributes to tumor evolution and therapy resistance are not fully understood.
- Understanding APOBEC's role is crucial for developing effective cancer treatments.
Purpose Of The Study
- To investigate the role of APOBEC mutagenesis in acquired therapy resistance in EGFR-mutant non-small cell lung cancer (NSCLC).
- To elucidate the functional impact of APOBEC3 expression on drug-tolerant persister cells (DTPs) and resistance evolution.
- To explore potential therapeutic targets related to APOBEC-driven resistance.
Main Methods
- Investigated APOBEC3 expression and activity in a model of EGFR-mutant NSCLC treated with EGFR inhibitors.
- Assessed the functional role of APOBEC3B in promoting DTP survival and resistance acquisition.
- Analyzed the association between APOBEC3B, squamous transdifferentiation, and the transcription factor ΔNp63.
- Utilized gene knockout strategies (p63) to evaluate therapeutic sensitization.
Main Results
- EGFR inhibition rapidly induced APOBEC3 expression and activity in lung cancer cells.
- APOBEC3 expression enhanced the survival of DTPs following EGFR inhibition.
- Constitutive APOBEC3B expression promoted resistance to gefitinib, favoring T790M mutation and squamous transdifferentiation.
- APOBEC3B expression correlated with increased ΔNp63 and squamous cell transdifferentiation.
- p63 knockout reduced ΔNp63 target gene expression and sensitized resistant cells to osimertinib.
Conclusions
- APOBEC activity promotes acquired therapy resistance in NSCLC by facilitating DTP evolution and squamous transdifferentiation.
- Targeting ΔNp63 presents a potential therapeutic strategy for gefitinib-resistant lung cancers.
- These findings highlight APOBEC's critical role in cancer progression and resistance, suggesting novel avenues for treatment.
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