title: DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity.
abstract: The encouraging response rates of BRCA1- and BRCA2-mutated cancers toward PARP inhibitors make it worthwhile to identify other potential determinants of PARP inhibitor responsiveness. Since the Fanconi anemia (FA) pathway coordinates several DNA repair pathways, including homologous recombination in which BRCA1 and BRCA2 play important roles, we investigated whether this pathway harbors other predictors of PARP inhibitor sensitivity. Lymphoblastoid cell lines derived from individuals with FA or clinically related syndromes, such as Warsaw breakage syndrome, were tested for PARP inhibitor sensitivity. Remarkably, we found a strong variability in PARP inhibitor sensitivity among different FANCD1/BRCA2-deficient lymphoblasts, suggesting that PARP inhibitor response depends on the type of FANCD1/BRCA2 mutation. We identified the DNA helicases FANCM and DDX11 as determinants of PARP inhibitor response. These results may extend the utility of PARP inhibition as effective anticancer treatment.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Stoepker
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Atiq
authors.initials: A
authors.lastname: Faramarz
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Rooimans
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Saskia E
authors.initials: SE
authors.lastname: van Mil
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Jesper A
authors.initials: JA
authors.lastname: Balk
authors.affiliation: Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Children's Hospital, University Hospital of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Eunike
authors.initials: E
authors.lastname: Velleuer
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Najim
authors.initials: N
authors.lastname: Ameziane
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Electronic address: h.t.riele@nki.nl.
authors.forename: Hein
authors.initials: H
authors.lastname: Te Riele
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics; D002461:Cell Line, Transformed; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000235:genetics; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D010793:Phthalazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; C506932:KU0058948; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C518295:FANCM protein, human; D004265:DNA Helicases; C101830:DDX11 protein, human; D053487:DEAD-box RNA Helicases
keywords: DDX11; FANCM; Fanconi anemia; PARP inhibitor; Sister chromatid cohesion; Warsaw breakage syndrome