title: CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy.
abstract: Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G2 arrest in the p53-deficient HNSCC cell lines, HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV(+) patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total, and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. ©2016 AACR.
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom. holly.barker@icr.ac.uk.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Barker
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom.
authors.forename: Radhika
authors.initials: R
authors.lastname: Patel
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom. Radiation Oncology Unit, University Hospital, Brest, France.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schick
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom. Head and Neck Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Head and Neck Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.affiliation: Head and Neck Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Newbold
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom. Head and Neck Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Shreerang
authors.initials: S
authors.lastname: Bhide
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom. Head and Neck Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C577959:3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile; D000631:Aminopyridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017239:Paclitaxel