title: Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models.
abstract: BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL-selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2(High)/BCL-XL (Low) In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132-44. ©2016 AACR.
authors.affiliation: Oncology Biomarkers, Genentech, South San Francisco, California.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Punnoose
authors.affiliation: Oncology Development, AbbVie, Inc, North Chicago, Illinois.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: Research Pathology, Genentech, South San Francisco, California.
authors.forename: Franklin
authors.initials: F
authors.lastname: Peale
authors.affiliation: Oncology Discovery, AbbVie, Inc, North Chicago, Illinois.
authors.forename: Erwin R
authors.initials: ER
authors.lastname: Boghaert
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tan
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Amy
authors.initials: A
authors.lastname: Young
authors.affiliation: Oncology Discovery, AbbVie, Inc, North Chicago, Illinois.
authors.forename: Michael
authors.initials: M
authors.lastname: Mitten
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ingalla
authors.affiliation: Oncology Biomarkers, Genentech, South San Francisco, California.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Darbonne
authors.affiliation: Oncology Discovery, AbbVie, Inc, North Chicago, Illinois.
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.affiliation: Oncology Discovery, AbbVie, Inc, North Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Tapang
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California.
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.affiliation: INSERM UMR892, CNRS UMR6299, University of Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Maiga
authors.affiliation: Early Discovery Biochemistry, Genentech, South San Francisco, California.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.affiliation: INSERM UMR892, CNRS UMR6299, University of Nantes, Nantes, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Amiot
authors.affiliation: Oncology Discovery, AbbVie, Inc, North Chicago, Illinois.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California. dsampath@gene.com.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D000072224:Bcl-2-Like Protein 11; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; D000069286:Bortezomib; C579720:venetoclax