Fig. 6: Transcriptional addiction in HGG gives rise to a therapeutic index for CDK9i relative to normal astrocytes. | Nature Communications

Fig. 6: Transcriptional addiction in HGG gives rise to a therapeutic index for CDK9i relative to normal astrocytes.

From: Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

Fig. 6

a. Half-maximal inhibitory concentration of AZD4573 after 3-day exposure in respective cell lines. Comparison reflects p value of two-tailed Student’s t-test of mean IC50 values from neoplastic vs non-neoplastic cultures. Minimum n = 3 biologically independent replicates per cell line (n = 3 HSJD-DIPG007, n = 4 BT245, n = 5 SU-DIPG4, HSJD-GBM001, and RPE-NEO, n = 6 HSJD-GBM002, pcGBM2, NHA-hTERT, and NIH3T3, n = 8 SF8628). b. Western blot analysis of p-Pol II (Ser 2) and MCL1 after indicated exposure times to 50 nM AZD4573. Data represent single experiment. c. Caspase 3/7 activity over time following fixed 4 nM dose of AZD4573. Error bars indicate SEM from minimum 4 biological replicates per cell line (n = 4 HSJD-GBM001, NHA-hTERT, and NIH3T3, n = 5 SU-DIPG4 and HSJD-DIPG007). d. Half-maximal inhibitory concentrations and comparison as in (A) but measured 3 days after a single 8-hour drug exposure followed by drug washout. Comparison reflects p value of two-tailed Student’s t-test of mean IC50 values from neoplastic vs non-neoplastic cultures, minimum n = 2 biologically independent replicates per cell line (n = 2 HSJD-GBM002, n = 3 HSJD-GBM001, n = 5 pcGMB2 and RPE-NEO, n = 6 HSJD-DIPG007, NHA-hTERT, and NIH3T3). e. Cell viability measured at 3 days following 8-hour exposure to 5 nM AZD4573 (top) or 700 nM atuveciclib (bottom) +/− 4 Gy IR. Box plots display interquartile range, median, and whisker (minimum to maximum). Comparison reflects p value of two-tailed Student’s t-test, n = 6 biologically independent replicates. f. Relative ratio of co-cultured DIPG cells (HSJD-DIPG007) and normal astrocytes (NHA-hTERT) following fractionated radiotherapy and intermittent AZD4573 treatment as indicated by arrows. g. Quantification of (f) at day 10, p value of two-tailed Student’s t-test from n = 6 biologically independent replicates imaged 4 fields per replicate. Source data are provided as a Source Data file.

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