Fig. 5

APG-2449 synergizes with EGFR inhibitors and overcomes osimertinib-resistance when combined with osimertinib/trametinib in xenograft models. Combination treatments with APG-2449 and EGFR inhibitors were evaluated in an HCC827 CDX model (A; treated for 3 weeks, n = 5 per treatment group), NCI-H1975 CDX model (B; treated for 3 weeks, n = 5 per treatment group), and NSCLC PDX model LD1–0006-215,676 harboring EGFR^L858R_T790M and ROS1 fusion (C; treated for 61 days, n = 6 per treatment group) in mice. D, Tumor growth curve of NCI-H1975 CDX model rechallenged with APG-2449 plus osimertinib (Day 47- Day 67) upon disease progression from 21-day osimertinib treatment (Day 1-Day 21). E, Western blot analysis of EGFR and FAK downstream signaling in NCI-H1975 xenografts collected 4 hours after the last administration from tumor-bearing mice treated with indicated compounds for 2 weeks. Each lane represents an individual animal. F, Cell viability (IC₅₀) of PC-9 (parental) or PC-9/OR (osimertinib-resistant) cells treated with osimertinib at indicated concentrations for 3 days. Data are representative of 3 independent experiments and shown as the mean ± SEM of triplicates. ^****p < 0.0001. G, Cell viability of PC-9/OR cells treated with indicated compounds for 72 hours. H, PC-9/OR xenograft models were treated with the indicated compounds for 3 weeks (n = 5 per treatment group)