Figure 5 from Targeting PRMT5 Inhibitor–Induced Adaptation in Pancreatic Cancer with the RBM39 Degrader Indisulam

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Combined PRMT5 and RBM39 inhibition induced apoptosis. A, Cell-cycle distribution of PSN1 cells treated with the vehicle control (DMSO), 4 nmol/L JNJ-64619178, 200 nmol/L indisulam, or the combination of 4 nmol/L JNJ-64619178 and 200 nmol/L indisulam for 48 (left) and 72 hours (right). Cell-cycle distribution was determined by FACS of PI-stained cells (n = 3). Repeated measure one-way ANOVA with correction for multiple-testing according to the Tukey test. The P value is indicated or *, P < 0.05. B and C, Caspase-3/7 Assay of PSN1 cells treated with the indicated dosages of indisulam and JNJ-64619178 (B) or GSK-3326595 (C) for 48, 72, and 96 hours. The fold activation of caspase-3/7 is color-coded (n = 3). D, Panc-1 caspase reporter cells were treated with 8 nmol/L JNJ-64619178 and/or 400 nmol/L indisulam, or DMSO was used as the vehicle control. The green fluorescence intensity (caspase activation) normalized to cell count, DMSO control, and t = 0 is shown over time (left) at 96 hours (middle) and 120 hours (right). Ninety-six hours: Friedman test, P < 0.0001; 120 hours: Friedman test, P < 0.0001. The P value after Dunn multiple-comparison test is indicated: **, P < 0.01; ***, P < 0.001, n = 3. E, PSN1 caspase reporter cells were treated with PRMT5i (8 nmol/L JNJ-64619178 or 100 nmol/L MRTX1719) and/or 400 nmol/L indisulam. DMSO was used as the vehicle control. The green fluorescence intensity (caspase activation) normalized to cell count, DMSO control, and t = 0 is shown over time (left) at 96 hours (middle) and 120 hours (right). Ninety-six hours: Friedman test, P < 0.0001; 120 hours: Friedman test, P < 0.0001. Dunn multiple-comparison test: *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001, n = 3.