title: Synergistic induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma.
abstract: Diffuse large B cell lymphoma is generally treated by chemotherapy and there is an unmet medical need for novel targeted therapies or combination therapies. Using in vitro screening, we have identified the combination of ibrutinib, an inhibitor of the tyrosine kinase BTK, and AZD2014, an mTOR catalytic inhibitor, as being highly synergistic in killing ABC-subtype DLBCL cell lines. Simultaneous inhibition of BTK and mTOR causes apoptosis both in vitro and in vivo and results in tumor regression in a xenograft model. We identify two parallel mechanisms that underlie apoptosis in this setting: cooperative inhibition of cap-dependent translation, and the inhibition of an NF-κB/IL10/STAT3 autocrine loop. Combined disruption of these pathways is required for apoptosis. These data represent a rational basis for the dual inhibition of BTK and mTOR as a potential treatment for ABC-subtype DLBCL.
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Scott A
authors: SA
authors: Ezell
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Michele
authors: M
authors: Mayo
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Teeru
authors: T
authors: Bihani
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Suprawee
authors: S
authors: Tepsuporn
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Suping
authors: S
authors: Wang
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Melissa
authors: M
authors: Passino
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Shaun E
authors: SE
authors: Grosskurth
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Mike
authors: M
authors: Collins
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Julie
authors: J
authors: Parmentier
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Corinne
authors: C
authors: Reimer
authors: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Kate F
authors: KF
authors: Byth
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D009025:Morpholines; D046912:Multiprotein Complexes; D016328:NF-kappa B; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C585537:vistusertib; D016753:Interleukin-10; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D000225:Adenine