title: 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 CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79BWT/MYD88mutpatient-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/MYD88mutABC-DLBCL models.
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Paul
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Maurice
authors.initials: M
authors.lastname: Soujon
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Antje M
authors.initials: AM
authors.lastname: Wengner
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Zitzmann-Kolbe
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sturz
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Haike
authors.affiliation: Advanced Molecular Pathology Laboratory, Singapore Health Services Pte Ltd, 20 College Road, 169856 Singapore, Singapore.
authors.forename: Koh Hui
authors.initials: KH
authors.lastname: Keng Magdalene
authors.affiliation: Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 11 Hospital Drive, 169610 Singapore, Singapore.
authors.forename: Sze Huey
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lange
authors.affiliation: Advanced Molecular Pathology Laboratory, Singapore Health Services Pte Ltd, 20 College Road, 169856 Singapore, Singapore.
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Office of Education, Duke-NUS Graduate Medical School, 8 College Road, 169857 Singapore, Singapore.
authors.forename: Soon Thye
authors.initials: ST
authors.lastname: Lim
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.affiliation: Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany. Electronic address: ningshu.liu@bayer.com.
authors.forename: Ningshu
authors.initials: N
authors.lastname: Liu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C486018:PIK3CD protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000225:Adenine; C000589253:copanlisib
keywords: BCR; CARD11; DLBCL; MYD88; NF-κB; PI3Kα; PI3Kδ; copanlisib; follicular lymphoma; ibrutinib-resistance