title: Breaking the DNA damage response to improve cervical cancer treatment.
abstract: Every year, cervical cancer affects ∼500,000 women worldwide, and ∼275,000 patients die of this disease. The addition of platin-based chemotherapy to primary radiotherapy has increased 5-year survival of advanced-stage cervical cancer patients, which is, however, still only 66%. One of the factors thought to contribute to treatment failure is the ability of tumor cells to repair chemoradiotherapy-induced DNA damage. Therefore, sensitization of tumor cells for chemoradiotherapy via inhibition of the DNA damage response (DDR) as a novel strategy to improve therapy effect, is currently studied pre-clinically as well as in the clinic. Almost invariably, cervical carcinogenesis involves infection with the human papillomavirus (HPV), which inactivates part of the DNA damage response. This HPV-mediated partial inactivation of the DDR presents therapeutic targeting of the residual DDR as an interesting approach to achieve chemoradio-sensitization for cervical cancer. How the DDR can be most efficiently targeted, however, remains unclear. The fact that cisplatin and radiotherapy activate multiple signaling axes within the DDR further complicates a rational choice of therapeutic targets within the DDR. In this review, we provide an overview of the current preclinical and clinical knowledge about targeting the DDR in cervical cancer.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hylke W
authors.initials: HW
authors.lastname: Wieringa
authors.affiliation: Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: m.vugt@umcg.nl.
authors.forename: Marcel A T M
authors.initials: MA
authors.lastname: van Vugt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy* / Q000821:virology; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D018816:Genes, cdc; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors / Q000502:physiology; D027383:Papillomaviridae / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D030361:Papillomavirus Infections / Q000628:therapy / Q000821:virology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects; D017211:Treatment Failure; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D002945:Cisplatin
keywords: Cervical cancer; Cisplatin; DDR-inhibitors; DNA damage response; Radiotherapy