APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer.
Nina Marie G GarciaJessica N BecerraBrock J McKinneyAshley V DiMarcoFeinan WuMatthew FitzgibbonJames V AlvarezPublished in: bioRxiv : the preprint server for biology (2023)
APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of ΔNp63 in gefitinib-resistant cells reduces the expression of the p63 target genes IL1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.
Keyphrases
- poor prognosis
- small cell lung cancer
- epidermal growth factor receptor
- induced apoptosis
- squamous cell
- long non coding rna
- cell cycle arrest
- tyrosine kinase
- crispr cas
- transcription factor
- endoplasmic reticulum stress
- oxidative stress
- binding protein
- cell death
- stem cells
- gene expression
- drinking water
- high resolution
- lymph node metastasis
- free survival
- papillary thyroid
- sensitive detection
- adverse drug
- smoking cessation