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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.

Author information

1
Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
2
Advanced Molecular Pathology Laboratory, Singapore Health Services Pte Ltd, 20 College Road, 169856 Singapore, Singapore.
3
Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 11 Hospital Drive, 169610 Singapore, Singapore.
4
Office of Education, Duke-NUS Graduate Medical School, 8 College Road, 169857 Singapore, Singapore.
5
Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany. Electronic address: ningshu.liu@bayer.com.

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 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.

KEYWORDS:

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

PMID:
28073005
DOI:
10.1016/j.ccell.2016.12.003
[Indexed for MEDLINE]
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