Fig. 8. Combination treatment targeting Notch and PKC in cells sensitive to NOTCHi.

a NOD/SCID mice were injected with 1 × 10⁶ PDTALL19 cells on day 1. On day 7, the mice were randomized and treated with vehicle (CTRL), GSI (DBZ: dibenzazepine), sotrastaurin (SOTRA) or sostrastaurin + DBZ. DBZ was administered in a 4 days on/3 days off regimen (4 doses in total). Sotrastaurin was administered in a regimen of 5 days on/2 days off (5 doses in total). Flow cytometry analysis of human Cd7⁺ cells in peripheral blood was performed on day 7, 11, 14, and 15 (sacrifice day). The values showed are mean ± SEM and significance were assessed by unpaired two-sided t test and. Vehicle n = 6 biologically independent mice; DBZ n = 3; sotrastaurin n = 5; sotrastaurin + DBZ n = 6. Gating strategies are provided in Supplementary Fig. 12. b Spleen weight (top) and size (bottom) after mice sacrifice after 15 days from PDTALL19 injection. The values showed are mean ± SEM and significance were assessed by unpaired two-sided t test. Vehicle n = 10 biologically independent mice; DBZ n = 3; sotrastaurin n = 3; sotrastaurin + DBZ n = 6. c Kaplan–Meier survival curves for PDTALL19. Significance was assessed by a two-sided log-rank (Mantel-Cox) test. Vehicle n = 10 biologically independent mice; DBZ n = 5; sotrastaurin n = 8; sotrastaurin + DBZ n = 5. d DND-41 were pretreated with sotrastaurin (5 μM) for 3 days. Next, GSI treatment (0.5 μM) was performed up to 5 weeks for three different populations: persister cells (DMSO + GSI), sotrastaurin washout (DMSO + GSI), and sotrastaurin (SOTRA + GSI). Live cell count was performed by trypan blue exclusion. n = 2 independent experiments for persister and persister/sotrastaurin; n = 1 for sotrastaurin washout. e Cells were harvested at different time points (2–5 weeks) and immunoblotted with the indicated antibodies. 5a and 5b indicate two-time points within week 5. The experiment was performed once. W/O washout. Source data are provided as Source Data file.