DEGRADATION OF XIAP AS A NOVEL TREATMENT STRATEGY IN HIGH-RISK NEUROBLASTOMA

The potential of XIAP antagonism as a treatment strategy for neuroblastoma has not been investigated despite neuroblastoma being an embryonal cancer with a developmental biology requiring XIAP. Here, we showed that the targeting of XIAP, and not other IAP members such as c-IAPs, was necessary to trigger apoptotic death in neuroblastoma, and that this was effected specifically via degradation and not inhibition. ARTS mimetic A4, a newly-identified XIAP-specific antagonist, was found to be highly potent towards neuroblastoma cells, and is tolerable and non-toxic towards non-cancerous normal cells, in comparison to pan-IAP antagonists. A4 catalyzed rapid degradation of XIAP through a ubiquitin-proteasomal pathway, worked synergistically with standard-of-care cytotoxic agents and prolonged the overall survival of high-risk MYCN-amplified neuroblastoma patient-derived xenografts. Collectively, this presents the degradation of XIAP mediated by ARTS mimetics as a potential therapeutic strategy for treatment of neuroblastoma, specifically aggressive high-risk MYCN-amplified disease which intrinsically overexpresses XIAP.

Author dc:creator

• CHOO ZHANG'E

• Neuroblastoma, XIAP, apoptosis, treatment, degradation, ARTS mimetic