Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT

Compared with follicular lymphoma, high PI3K alpha expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3K delta. Simultaneous inhibition of PI3K alpha and PI3K delta dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3K delta, PI3K alpha, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-KB activation driven by CD79(mu)t, CARD11(mut), TNFAIP3(mut), or MYD88(mut). Inhibition of PI3K alpha/delta resulted in tumor regression in an ibrutinib-resistant CD79B(WT)/MYD88(mut) patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79B(mut)-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3K alpha/delta inhibitor copanlisib produced a sustained complete response in vivo in CD79B(mut)/MYD88(mut) ABC-DLBCL models.