Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma

Mol Cancer Ther. 2021 Aug;20(8):1400-1411. doi: 10.1158/1535-7163.MCT-20-0710. Epub 2021 Jun 4.


Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2-dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma is a heterogenous pediatric cancer with a 5-year survival rate of less than 50% for high-risk patients, which includes nearly all cases with amplified MYCN We previously demonstrated that venetoclax is active in MYCN-amplified neuroblastoma but has limited single-agent activity in most models, presumably the result of other pro-survival BCL-2 family protein expression or insufficient prodeath protein mobilization. As the relative tolerability of venetoclax makes it amenable to combining with other therapies, we evaluated the sensitivity of MYCN-amplified neuroblastoma models to rational combinations of venetoclax with agents that have both mechanistic complementarity and active clinical programs. First, the MDM2 inhibitor NVP-CGM097 increases the prodeath BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified neuroblastomas to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified neuroblastoma through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Finally, the standard-of-care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of neuroblastoma, thus setting the stage for robust combination efficacy with venetoclax. In all cases, these rational combinations translated to in vivo tumor regressions in MYCN-amplified patient-derived xenograft models. Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). Although establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in patients with amplified MYCN with neuroblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Cell Proliferation
  • Cyclophosphamide / administration & dosage
  • Female
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • N-Myc Proto-Oncogene Protein / genetics*
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Sulfonamides / administration & dosage
  • Topotecan / administration & dosage
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Bridged Bicyclo Compounds, Heterocyclic
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Sulfonamides
  • Topotecan
  • Cyclophosphamide
  • venetoclax

Associated data