title: PARP1 impact on DNA repair of platinum adducts: preclinical and clinical read-outs.
abstract: Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA. We evaluated the effect of PARP inhibition on DNA repair functionality in a panel of cisplatin cell lines treated by the clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) and the commercially available inhibitor PJ34 (phenanthridinone). We determined PARP1 protein expression in whole tumor sections from the International Adjuvant Lung cancer Trial (IALT)-bio study and tested a 3-marker PARP1/MSH2/ERCC1 algorithm combining PARP1 tumor status with previously published data. Chemosensitivity of cisplatin in NSCLC cell lines was correlated with the accumulation of cisplatin DNA adducts (P=0.0004). Further, the pharmacological inhibition of PARP induced a 1.7 to 2.3-fold increase in platinum adduct accumulation (24h) in A549 cell line suggesting a slow-down of platinum DNA-adduct repair capacity. In parallel, PARP1 inhibition increased the sensitivity to cisplatin treatment. In patient samples, PARP1 expression levels did not influence patient survival or the effect of platinum-based post-operative chemotherapy in the global IALT-bio population (interaction P=0.79). Among cases with high expression of all three markers (triple positive), untreated patients had prolonged survival with a median DFS of 7.8 years, (HR=0.34, 95%CI [0.19-0.61], adjusted P=0.0003) compared to triple negative patients (1.4 years). Remarkably, triple positive patients suffered from a detrimental effect (4.9-year reduction of median DFS) by post-operative cisplatin-based chemotherapy (HR=1.79, 95%CI [1.01-3.17], adjusted P=0.04, chemotherapy vs. control). Combinatorial sub-group analysis of the 3 markers further suggested that PARP1 tumor positivity might constitute a molecular context with high theranostic interest of ERCC1 and MSH2 in NSCLC. In conclusion, our data confirm that platinum DNA adduct accumulation is linked to chemosensitivity, which increase by pharmacological PARP inhibitors points to a role of PARP-dependent DNA repair in the process. We further suggest DNA repair biomarkers should be analyzed in a larger context of multiple DNA repair pathway regulation.
authors: INSERM U981, Institut Gustave Roussy, DHU TORINO, Villejuif, France. ken.olaussen@igr.fr
authors: Ken A
authors: KA
authors: Olaussen
authors: Julien
authors: J
authors: Adam
authors: Elsa
authors: E
authors: Vanhecke
authors: Philippe
authors: P
authors: Vielh
authors: Robert
authors: R
authors: Pirker
authors: Luc
authors: L
authors: Friboulet
authors: Helmut
authors: H
authors: Popper
authors: Angélique
authors: A
authors: Robin
authors: Fréderic
authors: F
authors: Commo
authors: Jürgen
authors: J
authors: Thomale
authors: Louis
authors: L
authors: Kayitalire
authors: Martin
authors: M
authors: Filipits
authors: Thierry
authors: T
authors: Le Chevalier
authors: Fabrice
authors: F
authors: André
authors: Elisabeth
authors: E
authors: Brambilla
authors: Jean-Charles
authors: JC
authors: Soria
mesh_terms: D002227:Carbazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D004720:Endonucleases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D010797:Phthalimides / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis
chemical_list: C523456:CEP 8983; D002227:Carbazoles; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D010797:Phthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C057270:cisplatin-DNA adduct; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C071447:ERCC1 protein, human; D004720:Endonucleases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D002945:Cisplatin