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

A subset of cancers across multiple histologies with predominantly poor outcomes use the alternative lengthening of which can be identified with robust biomarkers. ALT has been reported to be prevalent in high-risk neuroblastoma and certain sarcomas, and ALT cancers are a major clinical found ALT in a variety of pediatric and adult cancer histollines from neuroblastomas, sarcomas, and carcinomas were hypersensitive to the p53 reactivator eprenetapopt (APR-246) telomere damage signaling in ALT cells activated ataxiawhich resulted in selective ALT sensitivity to APR-246. Treatplete responses in mice xenografted with ALT neuroblastoma, rhabdomyosarcoma, and breast cancer and delayed tumor growth in ALT colon cancer xenografts, while the combination had limited efficacy in TA thorn tumor models. A large number of adult and pediatric cancers present with the ALT phenotype, which confers a uniquely high sensitivity to reactivation of p53. These data support clinical evaluation of a combinatorial approach using APR-246 and irinotecan in ALT patients with cancer.

Automated summary

A subset of cancers across different tissue types show poor outcomes and can be identified with robust biomarkers. ALT, a specific cell activity, is commonly found in high-risk neuroblastoma and certain sarcomas, and reactivating p53 has shown to increase sensitivity to this cell activity. These findings support the clinical evaluation of specific drugs in ALT cancer patients.