Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53

EMBO Molecular Medicine

Chris T. Williamson⁵  Eiji Kubota⁵  Jeffrey D. Hamill²  Alexander Klimowicz⁴  Ruiqiong Ye⁵  Huong Muzik⁴  Michelle Dean⁴  LiRen Tu³  David Gilley³  Anthony M. Magliocco⁴  Bruce C. McKay²  D. Gwyn Bebb¹ 

[1] E-mail address: 关键词: ATM;    DNA‐PK;    olaparib;    p53;    PARP;   

DOI  :  10.1002/emmm.201200229

来源: Wiley

【 摘 要 】

Abstract

Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies.

【 授权许可】

Unknown   
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