Fig. 3: APOBEC3B drives targeted therapy resistance in mouse and human preclinical models.
From: The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance
a, TetO-EGFRL858R;CCSP-rtTA;R26LSL-APOBEC3B/Cre-ER(T2) mice with or without induction of subclonal APOBEC3B (A3B) with TKI therapy (erlotinib). b, Fraction of tumor grade, not present or hyperplasia only. Bronchioloalveolar adenoma or carcinoma at 5 months (Ei, n = 19; EA3Bi, n = 19; two-sided Fisher’s exact test, **P = 0.0044). c, Tumor nodules per lung section per mouse at 5 months (Ei, n = 19; EA3Bi, n = 19; two-sided Mann–Whitney test, *P = 0.0443). d, Tumor area per lung area per mouse at 5 months (Ei, n = 19; EA3Bi, n = 19; two-sided Mann–Whitney test, *P = 0.0212). e, Representative IHC staining of EGFRL858R and A3B (scale bar = 100 µm and 20 µm; Ei, n = 19; EA3Bi, n = 19 biological replicates). f, A3B+ cells per mm2 of tumor per mouse (EA3Bi −TKI = 151, EA3Bi +TKI = 52, two-sided Mann–Whitney test, ****P < 0.0001). g, Induction of subclonal A3B using TetO-EGFRL858R;CCSP-rtTA;R26Cre-ER(T2)/+ or TetO-EGFRL858R;CCSP-rtTA;R26LSL-APOBEC3B/Cre-ER(T2) mice with continuous TKI therapy (erlotinib). h, Tumor nodules per lung section per mouse (Ei, n = 13; EA3Bi, n = 17; two-sided Mann–Whitney test, **P = 0.0086). i, Fraction of tumor grade, not present or hyperplasia only. Bronchioloalveolar adenoma or carcinoma at 11 months (Ei, n = 13; EA3Bi, n = 17; two-sided Fisher’s exact test). j, Quantification of UNG+ cells per mm2 of tumor at 5 months postinduction (E, n = 10; EA3Bi, n = 10; two-tailed t test, *P = 0.0226, each dot represents a tumor). k, Representative IHC staining of EGFRL858R and UNG. Scale bar = 50 µm. l–n, CellTiter-Glo viability timecourse assays performed on A3B-deficient or A3B-proficient PC9 cells treated with 100 nM Osi (l, n = 3 biological replicates, mean ± s.d., two-sided t test, *P = 0.0439, *P = 0.0155, *P = 0.0168); HCC827 cells treated with 100 nM Osi (m, n = 3 biological replicates, mean ± s.d., two-sided t test, *P = 0.0377, **P = 0.0029, ****P = 0.0004, ****P = 0.00009); H3122 cells treated with 100 nM alectinib (n, n = 3 biological replicates, mean ± s.d., two-sided t test, *P = 0.0189, **P = 0.0044). Osi, osimertinib.
