title: High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition.
abstract: The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression.
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Laurel T
authors.initials: LT
authors.lastname: Bate-Eya
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ilona J M
authors.initials: IJ
authors.lastname: den Hartog
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ida
authors.initials: I
authors.lastname: van der Ploeg
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Schild
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Santo
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Westerhout
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.affiliation: Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M Emmy M
authors.initials: ME
authors.lastname: Dolman
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595707:BCL2 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D045304:Cytochromes c; C579720:venetoclax
keywords: ABT199; BCL-2; MCL-1; neuroblastoma; resistance