title: PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas.
abstract: Cancer including melanoma may be ''addicted" to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug.
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Czyż
authors.affiliation: Department of Molecular Genetics, University of Lodz, 90-236 Lodz, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Toma
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gajos-Michniewicz
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Majchrzak
authors.affiliation: Department of Flow Cytometry, Medical Center for Postgraduate Education, 01-813 Warsaw, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Hoser
authors.affiliation: Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Szemraj
authors.affiliation: Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.affiliation: Department of Dermatology, Faculty of Medicine, University Hospital Zürich, and University of Zürich, CH-8952, Zürich, Switzerland.
authors.forename: Phil
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gritsyuk
authors.affiliation: Department of Dermatology, Faculty of Medicine, University Hospital Zürich, and University of Zürich, CH-8952, Zürich, Switzerland.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, Faculty of Medicine, University Hospital Zürich, and University of Zürich, CH-8952, Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Molecular Genetics, University of Lodz, 90-236 Lodz, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sliwinski
authors.affiliation: Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D000072481:DNA Ligase ATP / Q000172:deficiency / Q000235:genetics*; D004260:DNA Repair; D003606:Dacarbazine / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D000072020:Synthetic Lethal Mutations; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; C000607893:LIG4 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D000072481:DNA Ligase ATP; C531550:olaparib
keywords: PARP1 inhibitor; melanoma; synthetic lethality