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

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

Cancer Cell. 2017 Jan 09;31(1):64-78

Authors: Paul J, Soujon M, Wengner AM, Zitzmann-Kolbe S, Sturz A, Haike K, Keng Magdalene KH, Tan SH, Lange M, Tan SY, Mumberg D, Lim ST, Ziegelbauer K, Liu N

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.

PMID: 28073005 [PubMed - indexed for MEDLINE]

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