Targeting BCL-2 Proteins in Pediatric Cancer: Dual Inhibition of BCL-X L and MCL-1 Leads to Rapid Induction of Intrinsic Apoptosis

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.

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Cat.No. Product Name Information
S7801 A-1331852 A-1331852 is a potent and selectiveBCL-XL inhibitor with Ki value less than 0.01 nM for BCL-XL and 6 nM, 4 nM, 142 nM for Bcl-2, Bcl-W, MCL-1 respectively. It may be useful in the treatment of cancer, immune and autoimmune diseases.

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