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

Abstract

Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79^mut, CARD11^mut, TNFAIP3^mut, or MYD88^mut. Inhibition of PI3Kα/δ 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 PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79B^mut/MYD88^mut ABC-DLBCL models.

Keywords: BCR; CARD11; DLBCL; MYD88; NF-κB; PI3Kα; PI3Kδ; copanlisib; follicular lymphoma; ibrutinib-resistance.