BRCA1, PARP1 and γH2AAX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Faraoni, Isabella^1,2  Compagnone, Mirco²  Lavorgna, Serena^2,3  Angelini, Daniela Francesca⁴  Cencioni, Maria Teresa⁴  Piras, Eleonora⁴  Panetta, Paola^2,3  Ottone, Tiziana^2,3  Dolci, Susanna³  Venditti, Adriano³  Graziani, Grazia¹  Lo-Coco, Francesco^2,3 

[1] Univ Roma Tor Vergata, Dept Syst Med, I-00133 Rome, Italy

[2] Santa Lucia Fdn IRCCS, Unit Neurooncohematol, Rome, Italy

[3] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy

[4] Santa Lucia Fdn IRCCS, Unit Neuroimmunol, Rome, Italy

关键词: Acute myeloid leukemia;    PARP1;    BRCA1;    H2AX;    PARP inhibitor;    Olaparib;   

DOI  :  10.1016/j.bbadis.2014.12.001

来源: Elsevier

【 摘 要 】

Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of acute myeloid leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (gamma H2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy. (C) 2014 Elsevier B.V. All rights reserved.

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