title: Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors.
abstract: Purpose:Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy.Experimental Design:We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells and three nontumor cells. In 12 breast cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways.Results:Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, nontumor cells do not show an increase of DNA damage nor lethality. Analysis of multilevel omics data from BC cells highlighted different DNA repair and cell-cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with six other PARPi in development.Conclusions:Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.Clin Cancer Res; 23(4); 1001-11. ©2016 AACR.
authors: Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.|Université Paris Sud, Université Paris-Saclay, CNRS, INSERM, Orsay, France.|DNA Therapeutics, Genopole, Evry, France.
authors: Wael
authors: W
authors: Jdey
authors: Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.|Université Paris Sud, Université Paris-Saclay, CNRS, INSERM, Orsay, France.
authors: Sylvain
authors: S
authors: Thierry
authors: Institut Curie, PSL Research University, INSERM, Paris, France.
authors: Christophe
authors: C
authors: Russo
authors: DNA Therapeutics, Genopole, Evry, France.
authors: Flavien
authors: F
authors: Devun
authors: National Institute of Health, National Cancer Institute, Bethesda, Maryland.
authors: Muthana
authors: M
authors: Al Abo
authors: DNA Therapeutics, Genopole, Evry, France.
authors: Patricia
authors: P
authors: Noguiez-Hellin
authors: DNA Therapeutics, Genopole, Evry, France.
authors: Jian-Sheng
authors: JS
authors: Sun
authors: Institut Curie, PSL Research University, INSERM, Paris, France.
authors: Emmanuel
authors: E
authors: Barillot
authors: Institut Curie, PSL Research University, INSERM, Paris, France.
authors: Andrei
authors: A
authors: Zinovyev
authors: Institut Curie, PSL Research University, INSERM, Paris, France.
authors: Inna
authors: I
authors: Kuperstein
authors: National Institute of Health, National Cancer Institute, Bethesda, Maryland.
authors: Yves
authors: Y
authors: Pommier
authors: Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France. marie.dutreix@curie.fr.|Université Paris Sud, Université Paris-Saclay, CNRS, INSERM, Orsay, France.
authors: Marie
authors: M
authors: Dutreix
mesh_terms: D045744:Cell Line, Tumor; D059766:DNA End-Joining Repair / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D051135:Rad51 Recombinase / Q000235:genetics; D000072020:Synthetic Lethal Mutations / Q000187:drug effects; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1 / Q000235:genetics
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D000076105:X-ray Repair Cross Complementing Protein 1; D011065:Poly(ADP-ribose) Polymerases; D051135:Rad51 Recombinase; C531550:olaparib