Fig. 1: SMARCA4/2 loss causes resistance to chemotherapeutics in ovarian and lung cancers.

The half maximal inhibitory concentration (IC₅₀) of cisplatin in pan cancer (a) and lung cancer (b) cell lines with differential mRNA expression for SMARCA4 and SMARCA2 (see Supplementary Fig. 2b for stratification). A4^H: SMARCA4^High; A4^L: SMARCA4^Low; A2^H: SMARCA2^High; A2^L: SMARCA2^Low. Cell line numbers are indicated in gray below each group. One-way ANOVA Kruskal–Wallis test followed by Dunn’s test for multiple comparisons to A4^HA2^H group, p values (p): a A4^HA2^L—0.5338, A4^LA2^H—0.0035, A4^LA2^L < 0.0001; b A4^HA2^L—0.4615, A4^LA2^H—0.0517, A4^LA2^L—0.0019. c Schematic outline of a pooled CRISPR screen with a sgRNA knockout library against epigenetic regulators to identify genes required for cisplatin response in OVCAR4 cells. d MAGeCK analysis^43,44,81 for screen in c. Genes were ranked by robust rank aggregation (RRA). Immunoblots (e), annexin V⁺/PI⁻ apoptotic cell population determined by flow cytometry (f), and representative phase-contrast images (g) of OVCAR4 cells with indicated SMARCA4/2 perturbations and cisplatin treatments (e, f 48 h). Immunoblots (h), annexin V⁺/PI⁻ apoptotic cell population (i), and representative phase-contrast images (j) of H1703 cells with indicated SMARCA4/2 perturbations and cisplatin treatments (h, i 72 h). e–j Ctrl Control, A4^KO SMARCA4 knockout, shA2 shRNA targeting SMARCA2, cl. PARP cleaved PARP, cl. caspase 3 cleaved caspase 3, A4 SMARCA4, A2 SMARCA2. Scale bar, 150 μm. Mean ± SD, n = 3 independent experiments, one-way ANOVA followed by Dunnett’s test for multiple comparisons, p values (p): f all (<0.0001); i A2 (0 μM)—0.0032, A4 (0 μM)—0.0023, A2 or A4 (3 μM) < 0.0001. **p < 0.01, ****p < 0.0001.