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. 2021 Apr 30;7(18):eabd4676. doi: 10.1126/sciadv.abd4676

Fig. 6. Analysis of GBM-enriched SEs uncovers actionable drug targets.

Fig. 6

(A) Engagement of GBM-enriched SE domains in druggable genome. (B) Chemical structure and biochemical activity of an MNK kinase inhibitor ETC-168. (C) Effect of ETC-168 on viability of GBM cells and GBM-propagating cells. (D and E) Effect of ETC-168 treatment on sphere formation capability (SFC) of GBM-propagating cells (i.e., NNI-11). (F) Effect of ETC-168 (5 μM) and TMZ (100 μM) on expression of downstream targets in NNI-11 cells after 24-hour treatment. (G) Effect of ETC-168 (5 μM) and temozolomide (TMZ; 100 μM) on viability of NNI-11 cells after 72-hour treatment. One-way ANOVA was used for analysis of significance. (H) Effect of ETC-168 [25 mg/kg, orally (po), twice a day (bid)] and TMZ (100 mg/kg, po, once a day (qd)] on expression of indicated proteins in orthotopic xenograft tumors (NNI-11) after 24-hour treatment. (I) Effect of ETC-168 and TMZ treatment on both survival of recipient mice with intracranial transplantation of NNI-11 cells and the tumor incidence at the end point of experiment. Log-rank test was applied for survival analysis; n = 6 or 7. (J and K) Effect of shRNA-mediated silencing of either MKNK1 or MKNK2 in NNI-11 cells on survival of recipient mice (J) and orthotopic tumor expansion 2 months after implantation (K). Log-rank test was applied for survival analysis in (J); n = 5 or 7. Error bars in (C) and (G) represent SEM; n = 3. IC50, half maximal inhibitory concentration.