fig7

Figure 7. Therapeutic targeting and clinical validation identify context-dependent metabolic adaptations associated with chemoresistance in HR+/HER2- BC. (A and B) Viability of parental and chemoresistant MCF-7 (A) and ZR-75-1 (B) cells following 72 h of treatment with IACS-010759 (1 and 0.005 µM, respectively); (C and D) Viability of parental and chemoresistant MCF-7 (C) and ZR-75-1 (D) cells following 72 h of treatment with mitoguazone (MGBG); (E and F) Viability of parental and chemoresistant MCF-7 (E) and ZR-75-1 (F) cells following 72 h of treatment with AMXT-1501; (G) Bubble plot showing the log₂ fold changes in ABCB1, ATP13A4, and SAT1 gene expression in post- vs. pre-NAC samples from patients with HR+/HER2- BC in the GSE191127 and GSE123845 RNA-sequencing datasets. Color indicates the direction and magnitude of the log₂ fold change; (H-L) Gene set enrichment analysis of post-NAC (surgery) vs. pre-NAC (baseline) samples from the GSE191127 dataset for ABC transporters (H), OXPHOS (I), glycolysis/gluconeogenesis (J), polyamine biosynthesis from arginine to putrescine (K), and GABA biosynthesis involving putrescine catabolism (L). Normalized enrichment scores (NES) and FDRs are indicated for each pathway. Data are presented as mean ± SEM from three independent biological experiments (n = 3), each performed with three technical replicate wells per condition (A-F). Individual data points represent the mean of the technical replicates from each independent biological experiment. Statistical significance was determined using two-way ANOVA with Sidák’s multiple comparison test (A-F). ^*P < 0.05; ^***P < 0.001; ns: not significant. HR+/HER2-: Hormone receptor-positive/human epidermal growth factor receptor 2-negative; BC: breast cancer; MGBG: methylglyoxal-bis(guanylhydrazone); NAC: neoadjuvant chemotherapy; ABC: ATP-binding cassette; OXPHOS: oxidative phosphorylation; GABA: γ-aminobutyric acid; NESs: normalized enrichment scores; FDRs: false discovery rates; SEM: standard error of the mean; ANOVA: analysis of variance; Doc-R: docetaxel-resistant; Epi-R: epirubicin-resistant; Pac-R: paclitaxel-resistant; ABCB1: ATP binding cassette subfamily B member 1; SAT1: spermidine/spermine N1-acetyltransferase 1.