Targeted Degradation of XIAP is Sufficient and Specific to Induce Apoptosis in MYCNoverexpressing High-risk Neuroblastoma

Zhang'E Choo, Xiaoying Koh, Megan Rui En Wong, Ruth Minothini Ashokan, Nurul Suhana Binte Ali Ahamed, Cong Bao Kang, Chik Hong Kuick, Kenneth Tou En Chang, Sarit Larisch, Amos Hong Pheng Loh, Zhi Xiong Chen

Research output: Contribution to journalArticlepeer-review


XIAP, the most potent mammalian inhibitor of apoptosis protein (IAP), critically restricts developmental culling of sympathetic neuronal progenitors, and is correspondingly overexpressed in most MYCN-amplified neuroblastoma tumors. Because apoptosis-related protein in the TGFβ signaling pathway (ARTS) is the only XIAP antagonist that directly binds and degrades XIAP, we evaluated the preclinical effectiveness and tolerability of XIAP antagonism as a novel targeting strategy for neuroblastoma. We found that antagonism of XIAP, but not other IAPs, triggered apoptotic death in neuroblastoma cells. XIAP silencing induced apoptosis while overexpression conferred protection from drug-induced apoptosis. From a screen of IAP inhibitors, first-in-class ARTS mimetic A4 was most effective against high-risk and high XIAP-expressing neuroblastoma cells, and least toxic toward normal liver- and bonemarrow-derived cells, compared with pan-IAP antagonists. On target engagement assays and nuclear magnetic resonance spectroscopy, A4 was observed to degrade rather than inhibit XIAP, catalyzing rapid degradation of XIAP through the ubiquitinproteasome pathway. In MYCN-amplified neuroblastoma patient-derived xenografts, A4 significantly prolonged survival as a single agent, and demonstrated synergismwith standard-of-care agents to reduce their effective required doses 3- to 6-fold. Engagement and degradation of XIAP by ARTS mimetics is a novel targeting strategy for neuroblastoma thatmay be especially effective against MYCN-amplified disease with intrinsically high XIAP expression. First-in-class ARTSmimetic A4 demonstrates preclinical efficacy and warrants further development and study. Significance: XIAP degradation is sufficient to kill MYCN-amplified neuroblastoma which overexpresses and relies on XIAP as a brake against cell death, without affecting normal cells.

Original languageEnglish
Pages (from-to)2386-2399
Number of pages14
JournalCancer Research Communications
Issue number11
StatePublished - 22 Nov 2023

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© 2023 The Authors.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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