Fig. 5: Targeting EGFR/MEKs/ERKs reverses BETi resistance. | Nature Communications

Fig. 5: Targeting EGFR/MEKs/ERKs reverses BETi resistance.

From: Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance

Fig. 5: Targeting EGFR/MEKs/ERKs reverses BETi resistance.

a Measurement of cell viability of MDA-MB231 and BT549 cells by CellTiter-Glo® luminescent viability assay. Control and RPS6KA2-knockdown cells were treated with JQ1 in the absence or presence of seven EGFR inhibitors for 48 h. 1: Ctr; 2: osimertinib; 3: AZ5104; 4: erlotinib; 5: icotinib; 6: gefitinib; 7: lapatinib; 8: EAI045; 9: RPS6KA2-shRNA; 10: JQ1; 11: JQ1 + osimertinib; 12: JQ1 + AZ5104; 13: JQ1 + erlotinib; 14: JQ1 + icotinib; 15: JQ1 + gefitinib; 16: JQ1 + lapatinib; 17: JQ1 + EAI045; 18: JQ1 + RPS6KA2-shRNA. Statistical data (Mean ± SD) are shown. P values were calculated between single JQ1-treated samples and samples treated with JQ1 plus EGFR inhibitors. Symbol ‘§’ indicates statistical significance (P < 0.05, one-way ANOVA). b MDA-MB-231 cells were treated with JQ1 (1 μM) and/or osimertinib, GDC0994, XMD8-92 (1 μM) or GDC0994/XMD8-92 for 12 h, western blotting was performed to detect JunD protein expression, and phosphorylated and total levels of MEK1/2, ERK1/2, ERK5 and RSK3. c CCK8 assays were done to measure the killing effects. Control and RPS6KA2-knockdown MDA-MB-231 and BT549 cells were treated with indicated the inhibitors for 48 h. 1: Control; 2: osimertinib; 3: BIX-02188; 4: U0126; 5: U0126 + BIX-02188; 6: GDC0994; 7: XMD8-92; 8: GDC0994 + XMD8-92; 9: RPS6KA2-shRNA; 10: JQ1; 11: JQ1 + osimertinib; 12: JQ1 + BIX-02188; 13: JQ1 + U0126; 14: JQ1 + BIX-02188 + U0126; 15: JQ1 + GDC0994; 16: JQ1 + XMD8-92; 17: JQ1 + GDC0994 + XMD8-92; 18: JQ1 + RPS6KA2-shRNA; 19: JQ1 + RPS6KA2-shRNA + BIX-02188 + U0126; 20: JQ1 + RPS6KA2-shRNA + GDC0994 + XMD8-92; 21: JQ1 + RPS6KA2-shRNA + osimertinib. Statistical data (mean±SD) are shown. P values were calculated when compared between single JQ1-treated samples and samples that were treated with JQ1 plus kinase inhibitors. Symbol ‘§’ indicates statistical significance (P < 0.05, one-way ANOVA). d CCK8 assay was performed to observe inhibition effects. Vector control and RSK3 (upper) or JunD-overexpressing (bottom) MDA-MB-231 cells were treated with the indicated inhibitors for 48 h. 1: DMSO; 2: JQ1; 3: JQ1 + osimertinib; 4: JQ1 + U0126; 5: JQ1 + BIX-02188; 6: JQ1 + BIX-02188 + U0126; 7: JQ1 + GDC0994; 8: JQ1 + XMD8-92; 9: JQ1 + GDC0994 + XMD8-92. Statistical data (mean±SD) are shown. P values were calculated when compared between JunD or RSK3-overexpression clones and vector controls in the presence of the same inhibitors. Symbol ‘§’ indicates statistical significance (P < 0.05, one-way ANOVA), and symbol ‘#’ indicates no significance (P > 0.05). Source data are provided as a Source Data file.

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