PI3Kα/δ and AKT inhibitors are active in molecular DLBCL subtypes. (A) Heat map of IC₅₀ concentrations for 16 inhibitors across 8 DLBCL cell lines. Red indicates resistance, whereas blue indicates sensitivity (IC₅₀ < 1 µM) to a specific compound. Doxorubicin and ibrutinib are used as positive control inhibitors. (B) Western blot analysis of PI3Kα and PI3Kδ isoform expression. Lysates from OCI-Ly1 cells are used on both blots to allow a comparison of basal protein expression. Representative results from at least 3 independent experiments are shown. (C) Western blot analysis of AKT phosphorylation and PTEN expression. Lysates from OCI-Ly1 cells are used on both blots to allow a comparison of basal protein expression. Representative results from at least 2 independent experiments are shown. (D) AZD8835 is predominantly effective in ABC DLBCL models, whereas AZD5363 induces cytotoxicity mostly in GCB DLBCL cell lines. Representative results from at least 3 independent experiments are shown. Error bars indicate standard deviations. (E) AZD5363 predominantly affects PTEN-deficient DLBCLs. Depiction of log₁₀-normalized IC₅₀ values demonstrates that PTEN-negative (red) DLBCL models are significantly more sensitive to AKT inhibition compared with PTEN-expressing (green) cell lines (P = .0056; 1-tailed Fisher’s exact test).