MALT1/MTORC1 combinations are highly synergistic against ABC-DLBCL. (A) ABC-DLBCL cell lines were treated for 1 hour with MI-2 (250 nM), C3 (1 μM), CAL-101 (1 μM), rapamycin (Rapa; 1 nM), or their combinations, as indicated, and proteins were extracted. Levels of phosphorylated and total proteins were evaluated by western blot. (B-D) Quantification of p-6/S6 levels (B), p-AKT/AKT levels (C) and Roquin p50/full length (D) for experiments in (A), respectively. Protein levels were normalized to actin and are relative to the average of vehicle-treated cells. Data are average ± standard error of the mean (SEM) of ≥2 independent experiments. (E) Dose response for temsirolimus (left panel) and rapamycin (right panel) in 4 ABC-DLBCL lines. Gray shaded area represents on-target dose. (F) Heat map of CIs at fraction affected 50% (Fa50) for C3 or MI-2 with temsirolimus or rapamycin in the indicated cell lines. (G-H) ZIP δ-score synergy plots for rapamycin in combination with MI-2 (G) or C3 (H) in the indicated cell lines and primary ABC-DLBCL specimens treated ex vivo in 3D organoids. *P < .05, **P < .01, ***P < .001, 1-way analysis of variance corrected for multiple comparisons 5% FDR. ns, not significant (P > .05).