title: Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.
abstract: Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Carla
authors.initials: C
authors.lastname: Morales
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Cooke
authors.affiliation: Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Manziello
authors.affiliation: Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Mount
authors.affiliation: Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Persky
authors.affiliation: Department of Medicine, Fox Chase Cancer Center - Temple Health, Philadelphia, Pennsylvania, United States of America.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.affiliation: Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Miller
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Qi
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002503:Centromere / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009361:Neoplasm Invasiveness; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D000069283:Rituximab; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001381:Azepines; C550258:MLN 8237; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D014750:Vincristine; D064127:Aurora Kinases