Fig. 3. OXPHOS targeting in cell lines and PDX models of palbociclib-resistant patients.
A Effect of IACS-010759 on in vitro models of ER+ breast cancer sensitive and resistant cells. Relative viability of MCF7 WT/LTED/ PalboR and of T47D WT/LTED derivatives cells treated for 72 h with IACS (10−11 to 10−4 M). Data represent mean survival fraction ±SEM relative to untreated cells (n = 3 independent experiments). Statistical analysis of MCF7 WT/LTED/PalboR was performed with the Two-way ANOVA test (Bonferroni corrected). Statistical analysis of T47D WT/LTED was performed with the unpaired multiple t-test. B Sensitive and resistant cells were subjected to Seahorse XFe96 Mito Stress Test and the ATP-dependent oxygen consumption rate (OCRATP)/extracellular acidification rate (ECAR) ratio was measured in real-time as an index of OXPHOS dependency. OCR and ECAR readings were determined for ten technical replicates from at least three biological replicates. Box and whisker plots with Min and Max values are represented. One-way ANOVA; Dunnett’s corrected. C Clinical history of patients corresponding to PDX HBCx-180 and HBCx-227. D In vivo response to fulvestrant and palbociclib, IACS-010759 and the combination of palbociclib + fulvestrant and IACS-010759 in HBCx-180 and HBCx-227 (mean ± SD). HBCx-180: n = 8 mice (control, IACS, palbo fulv + IACS) and n = 7 mice (palbo fulv). HBCx-227, n = 9 mice (control), n = 7 mice (IACS), n = 8 mice (palbo fulv), n = 5 mice (palbo fulv. + IACS). Mann–Whitney test, Two-tailed. RTV relative tumour volume. Source data are provided as a Source Data file. n number of mice.