p300 mediates early patterns of resistance to BETi in primary AML samples from a phase 1/2 clinical trial of molibresib. (A) Individual plots showing the treatment efficiency of concomitant or sequential treatment with BETi and p300i in 5 primary AML patient samples. Treatment efficacy was measured with CellTiterGlo at day 4 after the commencement of the first treatment. Shown are results from 2 biological replicates for each primary sample. For the sequential treatment mode with BETi first, p300i was added 48 hours after treatment commencement. (B) Violin plots showing treatment efficacy of concomitant or sequential treatment with BETi and p300i in 5 primary samples from patients with AML. Shown are results from 2 biological replicates for each primary sample. For the sequential treatment mode with BETi first, p300i was added 48 hours after treatment commencement. (C) Dot plots of average log2 fold expression changes of the indicated gene sets in 13 patients before and early after dose with molibresib in a phase 1/2 clinical trial. Negative values indicate a decrease in expression in the postdose samples. (D) Violin plots of the average log2 fold expression changes of the indicated genes in 13 patients before and early after dose with molibresib in a phase 1/2 clinical trial. Negative values indicate a decrease in expression in the postdose samples. (E) Viability after treatment with p300i (either 200 nM [upper] or 1000 nM [lower]) or DMSO in primary samples from the molibresib trial at predose and 5 days (for 4 samples) or 10 days (only for patient Moli_BETi_006, for whom samples were obtained at both days 5 and 10) postdose. Shown is the percent viability (measured via CellTiterGlo) to DMSO-treated cells. Due to the limited cell numbers of this clinical trial sample, only 1 “biological” replicate could be obtained. (F-G) Individual examples of viability after treatment with p300i (200 or 1000 nM) or DMSO in the primary samples Moli_BETi_006 (F) or Moli_BETi_12 (G) from the molibresib trial at predose and 5 days (for both patients) or 10 days (only for patient Moli_BETi_006). Shown is the percentage viability (measured via CellTiterGlo) to DMSO-treated cells. (H) Changes in expression of MYC in the same exemplar patient samples Moli_BETi_006 and Moli_BETi_12 at 24 hours of treatment with 200 or 1000 nM of p300i. Shown are log2 FCs to DMSO-treated cells. d5, day 5.
Figure 7.

p300 mediates early patterns of resistance to BETi in primary AML samples from a phase 1/2 clinical trial of molibresib. (A) Individual plots showing the treatment efficiency of concomitant or sequential treatment with BETi and p300i in 5 primary AML patient samples. Treatment efficacy was measured with CellTiterGlo at day 4 after the commencement of the first treatment. Shown are results from 2 biological replicates for each primary sample. For the sequential treatment mode with BETi first, p300i was added 48 hours after treatment commencement. (B) Violin plots showing treatment efficacy of concomitant or sequential treatment with BETi and p300i in 5 primary samples from patients with AML. Shown are results from 2 biological replicates for each primary sample. For the sequential treatment mode with BETi first, p300i was added 48 hours after treatment commencement. (C) Dot plots of average log2 fold expression changes of the indicated gene sets in 13 patients before and early after dose with molibresib in a phase 1/2 clinical trial. Negative values indicate a decrease in expression in the postdose samples. (D) Violin plots of the average log2 fold expression changes of the indicated genes in 13 patients before and early after dose with molibresib in a phase 1/2 clinical trial. Negative values indicate a decrease in expression in the postdose samples. (E) Viability after treatment with p300i (either 200 nM [upper] or 1000 nM [lower]) or DMSO in primary samples from the molibresib trial at predose and 5 days (for 4 samples) or 10 days (only for patient Moli_BETi_006, for whom samples were obtained at both days 5 and 10) postdose. Shown is the percent viability (measured via CellTiterGlo) to DMSO-treated cells. Due to the limited cell numbers of this clinical trial sample, only 1 “biological” replicate could be obtained. (F-G) Individual examples of viability after treatment with p300i (200 or 1000 nM) or DMSO in the primary samples Moli_BETi_006 (F) or Moli_BETi_12 (G) from the molibresib trial at predose and 5 days (for both patients) or 10 days (only for patient Moli_BETi_006). Shown is the percentage viability (measured via CellTiterGlo) to DMSO-treated cells. (H) Changes in expression of MYC in the same exemplar patient samples Moli_BETi_006 and Moli_BETi_12 at 24 hours of treatment with 200 or 1000 nM of p300i. Shown are log2 FCs to DMSO-treated cells. d5, day 5.

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