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

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Apr 9

PMID 27056887

Citations 34

Authors

Laurel T Bate-Eya

Ilona J M den Hartog

Ida van der Ploeg

Linda Schild

Jan Koster

Evan E Santo

Ellen M Westerhout

Rogier Versteeg

Huib N Caron

Jan J Molenaar

M Emmy M Dolman

Affiliations

Soon will be listed here.

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.

Citing Articles

Venetoclax plus cyclophosphamide and topotecan in heavily pre-treated relapsed metastatic neuroblastoma: a single center case series.

De Ioris M, Fabozzi F, Del Bufalo F, Del Baldo G, Villani M, Cefalo M Sci Rep. 2023; 13(1):19295.

PMID: 37935707 PMC: 10630499. DOI: 10.1038/s41598-023-44993-9.

Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment.

Neely V, Manchikalapudi A, Nguyen K, Dalton K, Hu B, Koblinski J Int J Mol Sci. 2023; 24(17).

PMID: 37685889 PMC: 10487506. DOI: 10.3390/ijms241713082.

MEK inhibition causes BIM stabilization and increased sensitivity to BCL-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma.

Eleveld T, Vernooij L, Schild L, Koopmans B, Alles L, Ebus M Front Oncol. 2023; 13:1130034.

PMID: 36895472 PMC: 9990464. DOI: 10.3389/fonc.2023.1130034.

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM.

Peterziel H, Jamaladdin N, ElHarouni D, Gerloff X, Herter S, Fiesel P NPJ Precis Oncol. 2022; 6(1):94.

PMID: 36575299 PMC: 9794727. DOI: 10.1038/s41698-022-00335-y.

Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

Seneviratne J, Carter D, Mittra R, Gifford A, Kim P, Luo J Int J Cancer. 2022; 152(7):1399-1413.

PMID: 36346110 PMC: 10953412. DOI: 10.1002/ijc.34349.

References

Irwin M, Park J . Neuroblastoma: paradigm for precision medicine. Pediatr Clin North Am. 2014; 62(1):225-56. DOI: 10.1016/j.pcl.2014.09.015. View

Chou T, Talalay P . A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems. J Biol Chem. 1977; 252(18):6438-42. View

Souers A, Leverson J, Boghaert E, Ackler S, Catron N, Chen J . ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19(2):202-8. DOI: 10.1038/nm.3048. View

Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson J, Souers A . The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2013; 28(1):210-2. PMC: 3887407. DOI: 10.1038/leu.2013.216. View

Hauck P, Chao B, Litz J, Krystal G . Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737. Mol Cancer Ther. 2009; 8(4):883-92. DOI: 10.1158/1535-7163.MCT-08-1118. View

Iqbal J, Neppalli V, Wright G, Dave B, Horsman D, Rosenwald A . BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol. 2006; 24(6):961-8. DOI: 10.1200/JCO.2005.03.4264. View

Czabotar P, Lessene G, Strasser A, Adams J . Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2013; 15(1):49-63. DOI: 10.1038/nrm3722. View

Lamers F, Schild L, den Hartog I, Ebus M, Westerhout E, Ora I . Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer. 2012; 48(16):3093-103. DOI: 10.1016/j.ejca.2012.01.037. View

Czabotar P, Lee E, van Delft M, Day C, Smith B, Huang D . Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci U S A. 2007; 104(15):6217-22. PMC: 1851040. DOI: 10.1073/pnas.0701297104. View

10.

Chen S, Dai Y, Harada H, Dent P, Grant S . Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 2007; 67(2):782-91. DOI: 10.1158/0008-5472.CAN-06-3964. View

11.

Choudhary G, Al-Harbi S, Mazumder S, Hill B, Smith M, Bodo J . MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015; 6:e1593. PMC: 4669737. DOI: 10.1038/cddis.2014.525. View

12.

Green D, Kroemer G . The pathophysiology of mitochondrial cell death. Science. 2004; 305(5684):626-9. DOI: 10.1126/science.1099320. View

13.

Wei M, LINDSTEN T, Mootha V, Weiler S, Gross A, Ashiya M . tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 2000; 14(16):2060-71. PMC: 316859. View

14.

Twentyman P, LUSCOMBE M . A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity. Br J Cancer. 1987; 56(3):279-85. PMC: 2002206. DOI: 10.1038/bjc.1987.190. View

15.

Rudin C, Hann C, Garon E, Ribeiro de Oliveira M, Bonomi P, Camidge D . Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012; 18(11):3163-9. PMC: 3715059. DOI: 10.1158/1078-0432.CCR-11-3090. View

16.

Goldsmith K, Gross M, Peirce S, Luyindula D, Liu X, Vu A . Mitochondrial Bcl-2 family dynamics define therapy response and resistance in neuroblastoma. Cancer Res. 2012; 72(10):2565-77. PMC: 3354953. DOI: 10.1158/0008-5472.CAN-11-3603. View

17.

Sun X, MacFarlane M, Zhuang J, Wolf B, Green D, Cohen G . Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem. 1999; 274(8):5053-60. DOI: 10.1074/jbc.274.8.5053. View

18.

Gomez-Bougie P, Wuilleme-Toumi S, Menoret E, Trichet V, Robillard N, Philippe M . Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. Cancer Res. 2007; 67(11):5418-24. DOI: 10.1158/0008-5472.CAN-06-4322. View

19.

Zhang H, Nimmer P, Tahir S, Chen J, Fryer R, Hahn K . Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007; 14(5):943-51. DOI: 10.1038/sj.cdd.4402081. View

20.

Davids M, Letai A . Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012; 30(25):3127-35. PMC: 4979238. DOI: 10.1200/JCO.2011.37.0981. View