title: Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1.
abstract: Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning antiapoptotic proteins BCL2 and MCL1 are frequently expressed. Here we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find that clinical samples have frequent co-expression of MCL1 and BCL2, suggesting that therapeutic strategies targeting only one will lead to treatment failures owing to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest antitumor activity against most DLBCL lines and resulted in compensatory upregulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent antitumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.
authors.affiliation: Bio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Bio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: P
authors.initials: P
authors.lastname: Pongtornpipat
authors.affiliation: College of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tiutan
authors.affiliation: Department of Pathology, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Kendrick
authors.affiliation: Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: D O
authors.initials: DO
authors.lastname: Persky
authors.affiliation: Department of Pathology, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Rimsza
authors.affiliation: Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Puvvada
authors.affiliation: 1] Bio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA [2] Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA [3] Department of Pharmacology and Toxicology, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Schatz
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003497:Cyclic N-Oxides; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007212:Indolizines; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D013449:Sulfonamides; C553669:dinaciclib; C579720:venetoclax