Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-XL and MCL-1 leads to rapid induction of intrinsic apoptosis

Cancer Lett. 2020 Jul 10:482:19-32. doi: 10.1016/j.canlet.2020.02.041. Epub 2020 Mar 4.


With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-XL (A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-XL and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-XL and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-XL and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-XL and MCL-1 inhibition as treatment regime.

Keywords: A-1331852; Apoptosis; BCL-2 proteins; Rhabdomyosarcoma; S63845.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles / pharmacology*
  • Benzothiazoles / therapeutic use
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chick Embryo
  • Child
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Isoquinolines / pharmacology*
  • Isoquinolines / therapeutic use
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Osteosarcoma / drug therapy
  • Osteosarcoma / metabolism*
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rhabdomyosarcoma / drug therapy
  • Rhabdomyosarcoma / metabolism*
  • Sarcoma, Ewing / drug therapy
  • Sarcoma, Ewing / metabolism*
  • Thiophenes / pharmacology*
  • Thiophenes / therapeutic use
  • bcl-X Protein / metabolism


  • A-1331852
  • BCL2L1 protein, human
  • Benzothiazoles
  • Isoquinolines
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Pyrimidines
  • S63845
  • Thiophenes
  • bcl-X Protein
  • Caspases