Cytidine Deaminase Deficiency Reveals New Therapeutic Opportunities against Cancer.
Purpose:One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment. Cytidine deaminase (CDA) was reported to be downregulated in cells derived from patients with Bloom syndrome, a genetic disease associated with a strong predisposition to a wide range of cancers. The purpose of this study was to determine whether CDA deficiency could be associated with tumors from the general population and could constitute a predictive marker of susceptibility to antitumor drugs.Experimental Design:We analyzedCDAexpressionin silico, in large datasets for cancer cell lines and tumors and in various cancer cell lines and primary tumor tissues using IHC, PDXs, qRT-PCR, and Western blotting. We also studied the mechanism underlying CDA silencing and searched for molecules that might target specifically CDA-deficient tumor cells usingin silicoanalysis coupled to classical cellular experimental approaches.Results:We found that CDA expression is downregulated in about 60% of cancer cells and tissues. We demonstrate that DNA methylation is a prevalent mechanism of CDA silencing in tumors. Finally, we show that CDA-deficient tumor cells can be specifically targeted with epigenetic treatments and with the anticancer drug aminoflavone.Conclusions:CDA expression status identifies new subgroups of cancers, and CDA deficiency appears to be a novel and relevant predictive marker of susceptibility to antitumor drugs, opening up new possibilities for treating cancer.Clin Cancer Res; 23(8); 2116-26. ©2016 AACR.
Institut Curie, PSL Research University, UMR 3348, 91405 Orsay, France.|CNRS UMR 3348, Centre Universitaire, Bât. 110, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, UMR 3348, 91405 Orsay, France.
Hamza
H
Mameri
Institut Curie, Genetic Department, 26, rue d'Ulm, 75005 Paris, France.
Ivan
I
Bièche
Institut Curie, Platform of Investigative Pathology, 26, rue d'Ulm, 75005 Paris, France.
Didier
D
Meseure
Institut Curie, PSL Research University, Translational Research Department, 26, rue d'Ulm, 75005 Paris, France.
Elisabetta
E
Marangoni
Institut Curie, PSL Research University, UMR 3348, 91405 Orsay, France.|CNRS UMR 3348, Centre Universitaire, Bât. 110, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, UMR 3348, 91405 Orsay, France.
Géraldine
G
Buhagiar-Labarchède
Institut Curie, Platform of Investigative Pathology, 26, rue d'Ulm, 75005 Paris, France.|Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, 20892.
André
A
Nicolas
Institut Curie, Genetic Department, 26, rue d'Ulm, 75005 Paris, France.
Sophie
S
Vacher
Institut Curie, PSL Research University, UMR 3348, 91405 Orsay, France.|CNRS UMR 3348, Centre Universitaire, Bât. 110, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, UMR 3348, 91405 Orsay, France.
Rosine
R
Onclercq-Delic
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, 20892.
Vinodh
V
Rajapakse
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, 20892.
Sudhir
S
Varma
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, 20892.
William C
WC
Reinhold
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, 20892.
Yves
Y
Pommier
Institut Curie, PSL Research University, UMR 3348, 91405 Orsay, France. mounira.amor@curie.fr.|CNRS UMR 3348, Centre Universitaire, Bât. 110, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, UMR 3348, 91405 Orsay, France.
Mounira
M
Amor-Guéret
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000172:deficiency*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009369:Neoplasms / Q000201:enzymology*; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D003564:Cytidine Deaminase