Fig. 6.

SMARCA4/2 inhibition by FHD-286 induces ERBB signaling and sensitivity to afatinib in SCLC. A Proliferation curves of SCLC-A, -N, -P and -Y SCLC cell lines treated with FHD-286 for 96 h. The mean ± SD is shown. B Tumor growth of Lx151 and Lx95 SCLC PDXs implanted in NSG mice and treated with 1.5 mg/kg BID p.o. of FHD-286. Student’s two-tailed unpaired t test. ***p < 0.001. C IPA analysis on significantly upregulated genes in FHD-286-treated cells versus control untreated cells. D Immunoblot of ERBB family proteins in H146 and H82 cells after treatment with 100 nM of FHD-286 for 14 days. E Western blots of FHD-286 (100 nM) treated cells at the indicated times. F Synergy plots of FHD-286 and afatinib in NE SCLC cell lines. G Cell death quantification by flow cytometry at day 5 of H146 and H82 cells after treatment with FHD-286, afatinib or both. One way ANOVA followed by Bonferroni comparison test. ***p < 0.001, ****p < 0.0001. H Normalized tumor growth of Lx1042 (SCLC-N), Lx1322 (SCLC-P), Lx151 (SCLC-A) and Lx95 (SCLC-A) relative to day 1 of treatment. Two-way ANOVA followed by Bonferroni comparison test. *p < 0.05, **p < 0.01, ***p < 0.001. I Schematic representation of the role of SMARCA4 in sustaining the NE phenotype in SCLC