Roscovitine strongly enhances the effect of olaparib on radiosensitivity for HPV neg. but not for HPV pos. HNSCC cell lines

// Frank Ziemann 1 , Steve Seltzsam 1 , Kristin Dreffke 1 , Stefanie Preising 1 , Andrea Arenz 1 , Florentine S.B. Subtil 1 , Thorsten Rieckmann 2, 3 , Rita Engenhart-Cabillic 1 , Ekkehard Dikomey 1, 2 and Andrea Wittig 1 1 Department of Radiotherapy and Radiooncology, Philipps-University Marburg, University Hospital Giesen and Marburg, Marburg, Germany 2 Laboratory for Radiobiology & Experimental Radiooncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany 3 Department of Otolaryngology and Head and Neck Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany Correspondence to: Andrea Wittig, email: andrea.wittig@staff.uni-marburg.de Keywords: human papillomavirus; roscovitine; homologous recombination; ionizing radiation; HNSCC Received: June 03, 2017      Accepted: October 04, 2017      Published: October 24, 2017 ABSTRACT At present, advanced stage human Papillomavirus (HPV) negative and positive head and neck squamous cell carcinoma (HNSCC) are treated by intense multimodal therapy that includes radiochemotherapy, which are associated with relevant side effects. Patients with HPV positive tumors possess a far better prognosis than those with HPV negative cancers. Therefore, new therapeutic strategies are needed to improve the outcome especially of the latter one as well as quality of life for all HNSCC patients. Here we tested whether roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), which hereby also blocks homologous recombination (HR), can be used to enhance the radiation sensitivity of HNSCC cell lines. In all five HPV negative and HPV positive cell lines tested, roscovitine caused inhibition of CDK1 and 2. Surprisingly, all HPV positive cell lines were found to be defective in HR. In contrast, HPV negative strains demonstrated efficient HR, which was completely suppressed by roscovitine. In line with this, for HPV negative but not for HPV positive cell lines, treatment with roscovitine resulted in a pronounced enhancement of the radiation-induced G2 arrest as well as a significant increase in radiosensitivity. Due to a defect in HR, all HPV positive cell lines were efficiently radiosensitized by the PARP-1 inhibitor olaparib. In contrast, in HPV negative cell lines a significant radiosensitization by olaparib was only achieved when combined with roscovitine.