Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of diffuse large B-cell lymphoma

Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Ka/d) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor kappa-B (NF-kB) signaling, prompting us to combine AZD8835 with the Brutons tyrosine kinase (BTK) inhibitor ibrutinib. This combination was highly synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.

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Erdmann T, Klener P, Lynch JT, Grau M, Vočková P, Molinsky J, Tuskova D, Hudson K, Polanska UM, Grondine M, Mayo M, Dai B, Pfeifer M, Erdmann K, Schwammbach D, Zapukhlyak M, Staiger AM, Ott G, Berdel WE, Davies BR, Cruzalegui F, Trneny M, Lenz P, Barry ST, Lenz G