Extended Data Fig. 8: TKI-induced APOBEC activity and evolutionary history of evolving resistant clones.

a, A3A and A3B expression levels from RNA-seq (GSE75602) performed on parental PC9 cells, PC9 DTP cells after 14 days of gefitinib treatment (GP), early EGFR^T790M resistant clone PC9-GR2 and late EGFR^T790M resistant clone PC9-GR3 (previously described in Hata and Niederst et al.¹¹). PC9 cells were treated with gefitinib, PC9-GR2/GR3 cells were treated with the third-generation EGFR inhibitor WZ4002 (all for 24 h). b, Percentage of DDOST hotspot reads with A3A editing in PC9 and PC9-GR2/GR3 cells treated with gefitinib or WZ4002, respectively. c, A3A induction and suppression of EGFR downstream signaling. NSCLC cells were treated with or without 1 μM gefitinib, 1 μM osimertinib, 100 nM trametinib or 1 μM GDC0941 for 24 h. Expression of A3A was determined by quantitative RT-PCR (upper panel). Data are expressed as log₂ fold change relative to non-treated control (NT) (mean ± s.d. of 3 biological replicates). Western blot of AKT and ERK phosphorylation (lower panel). d, Summary of the relationship between EGFR signaling and A3A mRNA expression during targeted therapy in PC9 early and late resistant clones.