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Cancer Cell. 2017 Jan 9;31(1):64-78. doi: 10.1016/j.ccell.2016.12.003.

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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Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
Advanced Molecular Pathology Laboratory, Singapore Health Services Pte Ltd, 20 College Road, 169856 Singapore, Singapore.
Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 11 Hospital Drive, 169610 Singapore, Singapore.
Office of Education, Duke-NUS Graduate Medical School, 8 College Road, 169857 Singapore, Singapore.
Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany. Electronic address:


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 CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79BWT/MYD88mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79Bmut-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 CD79Bmut/MYD88mut ABC-DLBCL models.


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

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