Figure 7. p300 mediates early patterns of resistance to BETi in primary AML samples from a phase I/II clinical trial of Molibresib.

A. Individual plots showing 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 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 48hr after treatment commencement.

B. Violin plots showing treatment efficacy of concomitant or sequential treatment with BETi and p300i in 5 primary AML patient samples. Shown are results from 2 biological replicates for each primary sample. For the sequential treatment mode with BETi first, p300i was added 48hr after treatment commencement.

C. Dot plots of average log2 fold expression changes of the indicated gene sets in 13 patients pre- and early post-dose with Molibresib in a Phase 1/2 clinical trial. Negative values indicate a decrease in expression in the post-dose samples.

D. Violin plots of the average log2 fold expression changes of the indicated genes in 13 patients pre- and early post-dose with Molibresib in a Phase 1/2 clinical trial. Negative values indicate a decrease in expression in the post-dose samples.

E. Viability after treatment with p300i (either 200 nM - upper panel or 1000 nM -lower panel) or DMSO in primary samples from the Molibresib trial at pre-dose and 5 (for four samples) days or 10 (only for patient Moli_BETi_006, for whom samples were obtained at both day 5 and 10) days post-dose. Shown is the percent viability (measured via CellTiterGlo) to DMSO-treated cells. Due to the limited cell numbers of this clinical trial sample, only one “biological” replicate could be obtained.

F.-G. Individual examples of viability after treatment with p300i (200 nM or 1000 nM) or DMSO in the primary samples Moli_BETi_006 (F) or Moli_BETi_12 (G) from the Molibresib trial at pre-dose 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 hr of treatment with 200 nM or 1000 nM of p300i. Shown are log2 fold changes to DMSO-treated cells.