title: Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199).
abstract: As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2(High)) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2(High) cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2(High) NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2(Low) NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2(Low)) that could benefit from BCL-XL (navitoclax)-driven combination therapy.
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, IL, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Phillips
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, IL, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Lam
authors.affiliation: Abbott Molecular, Des Plaines, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Litvinovich
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Roberts-Rapp
authors.affiliation: Oncology Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: Oncology Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Leverson
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: C000611392:A-1210477; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C579720:venetoclax; C528561:navitoclax