TP53 loss‑of‑function mutations reduce sensitivity of acute leukaemia to the curaxin CBL0137.

Abstract

The presence of a TP53 mutation is a predictor of poor outcome in leukaemia, and efficacious targeted therapies for these patients are lacking. The curaxin CBL0137 has demonstrated promising antitumour activities in multiple cancers such as glioblastoma, acting through p53 activation, NF‑κB inhibition and chromatin remodelling. In the present study, it was revealed using Annexin‑V/7‑AAD apoptosis assays that CBL0137 has efficacy across several human acute leukaemia cell lines with wild‑type TP53, but sensitivity is reduced in TP53‑mutated subtypes. A heterozygous TP53 loss‑of‑function mutation in the KMT2A‑AFF1 human RS4;11 cell line was generated, and it was demonstrated that heterozygous TP53 loss‑of‑function is sufficient to cause a significant reduction in CBL0137 sensitivity. To the best of our knowledge, this is the first evidence to suggest a clinically significant role for functional p53 in the efficacy of CBL0137 in acute leukaemia. Future CBL0137 clinical trials should include TP53 mutation screening, to establish the clinical relevance of TP53 mutations in CBL0137 efficacy.

• Authors: Michelle O Forgione, Barbara J McClure, Elyse C Page, David T Yeung, Laura N Eadie, Deborah L White
• Journal: Oncology reports (Oncol Rep) Vol. 47 Issue 5 (May 2022) ISSN: 1791-2431 [Electronic] Greece
• PMID: 35323988 (Publication Type: Journal Article)

Chemical References

• CBLC137
• Carbazoles
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Carbazoles (pharmacology)
• Glioblastoma (drug therapy)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Mutation
• Tumor Suppressor Protein p53 (genetics)