title: ABT-737 is highly effective against molecular subgroups of multiple myeloma.
abstract: Multiple myeloma is a plasma cell malignancy that is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients. The Bcl-2 protein family is critical for myeloma cell survival. ABT-737 is a cell-permeant compound that binds to Bcl-2 and Bcl-x(L) but not to Mcl-1. Using a myeloma cell line collection (n = 25) representative of different molecular translocations, we showed that ABT-737 effectively kills a subset of cell lines (n = 6), with a median lethal dose ranging from 7 ± 0.4 nM to 150 ± 7.5 nM. Of interest, all sensitive cell lines harbored a t(11;14). We demonstrated that ABT-737-sensitive and ABT-737-resistant cell lines could be differentiated by the BCL2/MCL1 expression ratio. A screen of a public expression database of myeloma patients indicates that the BCL2/MCL1 ratio of t(11;14) and hyperdiploid patients was significantly higher than in all other groups (P < .001). ABT-737 first induced the disruption of Bcl-2/Bax, Bcl-2/Bik, or Bcl-2/Puma complexes, followed by the disruption of Bcl-2 heterodimers with Bak and Bim. Altogether, the identification of a subset of cell lines and primary cells effectively killed by ABT-737 alone supported the evaluation of ABT-263, an orally active counterpart to ABT-737, for the treatment of t(11;14) and hyperdiploid groups of myeloma harboring a Bcl-2(high)/Mcl-1(low) profile.
authors.affiliation: Inserm, Unité Mixte de Recherche_S892, Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Bodet
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Bougie
authors.forename: Cyrille
authors.initials: C
authors.lastname: Touzeau
authors.forename: Christelle
authors.initials: C
authors.lastname: Dousset
authors.forename: Géraldine
authors.initials: G
authors.lastname: Descamps
authors.forename: Sophie
authors.initials: S
authors.lastname: Maïga
authors.forename: Hervé
authors.initials: H
authors.lastname: Avet-Loiseau
authors.forename: Régis
authors.initials: R
authors.lastname: Bataille
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: Steven
authors.initials: S
authors.lastname: Le Gouill
authors.forename: Catherine
authors.initials: C
authors.lastname: Pellat-Deceunynck
authors.forename: Martine
authors.initials: M
authors.lastname: Amiot
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D019938:Cyclin D1