Fig. 7: APOBEC3B expression and APOBEC-associated mutations are elevated with targeted therapy in patients with NSCLC.

a, APOBEC3B (A3B) expression levels (batch-corrected transcripts per million (TPM)) measured using RNA-seq analysis in human NSCLC specimens driven by EGFR- and ALK-driver mutations obtained before TKI treatment (pre-TKI, n = 32 samples) or post-treatment (post-TKI, n = 42 samples; all data points shown, two-sided t test, *P = 0.02). b, APOBEC family member expression measured using single-cell RNA-seq obtained from human NSCLC before TKI treatment (TN), on-treatment at RD or at PD (all data points shown, n = 762, 553 and 988 cells per group, respectively, two-sided Wilcoxon test with a Holm correction, ****P < 2.22 × 10⁻¹⁶). c,d, Representative images of IHC analysis of A3B protein levels in patients with NSCLC at TN, RD and PD stages. Red arrows indicate positive stained cells (scale bar: 30 µM, c) with IHC quantification of human NSCLC samples pre-TKI (n = 16 samples) or post-TKI single agent (n = 15 samples; all data points shown, two-sided unpaired t test, *P = 0.0113, d). e, Total mutation burden (SNV count) in paired human NSCLC samples pre-TKI or post-TKI (n = 32, two-tailed Wilcoxon matched-pairs signed-rank test, **P = 0.0013). f, APOBEC-associated mutation count in paired human NSCLC samples pre-TKI or post-TKI (n = 32, two-tailed Wilcoxon matched-pairs signed-rank test, *P = 0.0155). g, Mutation signature associated with each putative de novo TKI resistance mutation detected in clinical samples analyzed post-TKI at PD. An asterisk denotes a sample from a patient who has received prior chemotherapy. Boxplots: middle line represents median; lower and upper hinges represent the first and third quartiles; lower and upper whiskers represent smallest and largest values within 1.5× interquartile range from hinges.