Data from Alternative Lengthening of Telomeres in Cancer Confers a Vulnerability to Reactivation of p53 Function

• DOI: 10.1158/0008-5472.c.6514106.v1
• Publication Date: 2023-03-31T21:16:10Z
• Authors: Shawn J. Macha; Balakrishna Koneru; Trevor A. Burrow; Charles Zhu; Dzmitry Savitski; Rakhshanda L. Rahman; Catherine A. Rona...; Jonas Nance; Kristyn McCoy; Cody Eslinger; C. Patrick Reynolds
• Keywords: Pediatric cancer

<div>Abstract<p>A subset of cancers across multiple histologies with predominantly poor outcomes use the alternative lengthening telomeres (ALT) mechanism to maintain telomere length, which can be identified robust biomarkers. ALT has been reported prevalent in high-risk neuroblastoma and certain sarcomas, are a major clinical challenge that lack targeted therapeutic approaches. Here, we found variety pediatric adult cancer histologies, including carcinomas. Patient-derived cell lines from neuroblastomas, carcinomas were hypersensitive p53 reactivator eprenetapopt (APR-246) relative telomerase-positive (TA<sup>+</sup>) models. Constitutive damage signaling cells activated ataxia-telangiectasia mutated (ATM) kinase phosphorylate p53, resulted selective sensitivity APR-246. Treatment APR-246 combined irinotecan achieved complete responses mice xenografted neuroblastoma, rhabdomyosarcoma, breast delayed tumor growth colon xenografts, while combination had limited efficacy TA<sup>+</sup> A large number present phenotype, confers uniquely high reactivation p53. These data support evaluation combinatorial approach using patients cancer.</p>Significance:<p>This work demonstrates constitutive activation ATM chemotherapy-refractory renders them function by APR-246, indicating potential strategy overcome resistance.</p></div>