Breaking the DNA damage response to improve cervical cancer treatment. (January 2016)

• Record Type: Journal Article
• Authors: Wieringa, Hylke W.; van der Zee, Ate G.J.; de Vries, Elisabeth G.E.; van Vugt, Marcel A.T.M.
• Is Part Of: Cancer treatment reviews. Volume 42(2016)
• Page Start: 30
• Page End: 40
• Publication Date: 2016-01
• Subjects: Cervical cancer -- Radiotherapy -- Cisplatin -- DNA damage response -- DDR-inhibitors; Cancer -- Periodicals; Cancer -- Treatment -- Periodicals; Neoplasms -- therapy -- Periodicals; Cancer -- Périodiques; Cancer -- Traitement -- Périodiques; Cancer -- Treatment; Electronic journals; Periodicals; 616.99406
• DOI: 10.1016/j.ctrv.2015.11.008
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: Combined chemoradiotherapy is standard of care for advanced cervical cancer. Chemoradiotherapy introduces DNA damage in tumor cells to induce cell death. Tumor cells activate the 'DNA damage response' to repair therapy-induced DNA damage. HPV partially impairs the cellular response to DNA damage in cervical cancer cells. Therapeutic targeting of residual DDR could 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.