G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1. 2017

Chia-Jung Busch, and Marie Sophie Kröger, and Jana Jensen, and Malte Kriegs, and Fruzsina Gatzemeier, and Cordula Petersen, and Adrian Münscher, and Kai Rothkamm, and Thorsten Rieckmann
Department of Otolaryngology and Head and Neck Surgery, University Medical Center Hamburg Eppendorf, Germany.

HPV-positive HNSCC cells are characterized by radiosensitivity, inefficient DNA double-strand break repair and a profound and prolonged arrest in G2. Here we explored the effect of clinically relevant inhibitors of Chk1 and Wee1 to inhibit the radiation-induced G2-arrest in order to achieve further radiosensitization. Assessment of Chk1 activity by Western blot; assessment of cell cycle distribution by propidium iodide staining and flow cytometry; assessment of cell survival by colony formation assay. HPV+ HNSCC cell lines: UD-SCC-2, UM-SCC-47 and UPCI-SCC-154; Chk1 inhibitors: LY2603618, MK8776; Wee1 inhibitor: AZD1775. Specific Chk1 inhibitors efficiently abrogated the radiation-induced G2-arrest and caused radiosensitization. Wee-inhibition by AZD1775 resulted in the activation of Chk1. This feedback mechanism is likely to counteract some of the effects of Wee1 inhibition but could be antagonized through the combined inhibition of both kinases. Combined inhibition was effective using profoundly reduced concentrations of both inhibitors and resulted in more efficient radiosensitization of the HPV-positive cell lines compared to p53 proficient normal human fibroblasts. Specific Chk1 inhibitors as well as the combined inhibition of Chk1 and Wee1 radiosensitize HPV-positive HNSCC cells.

UI MeSH Term Description Entries
D009687 Nuclear Proteins Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. Nucleolar Protein,Nucleolar Proteins,Nuclear Protein,Protein, Nuclear,Protein, Nucleolar,Proteins, Nuclear,Proteins, Nucleolar
D011505 Protein-Tyrosine Kinases Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors. Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D011838 Radiation-Sensitizing Agents Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells. Radiation Sensitizer,Radiosensitizing Agent,Radiosensitizing Agents,Agents, Radiation-Sensitizing,Radiation Sensitizers,Radiation Sensitizing Agents,Radiation-Sensitizing Drugs,Radiation-Sensitizing Effect,Radiation-Sensitizing Effects,Radiosensitizing Drugs,Radiosensitizing Effect,Radiosensitizing Effects,Agent, Radiosensitizing,Agents, Radiation Sensitizing,Agents, Radiosensitizing,Drugs, Radiation-Sensitizing,Drugs, Radiosensitizing,Effect, Radiation-Sensitizing,Effect, Radiosensitizing,Effects, Radiation-Sensitizing,Effects, Radiosensitizing,Radiation Sensitizing Drugs,Radiation Sensitizing Effect,Radiation Sensitizing Effects,Sensitizer, Radiation,Sensitizers, Radiation,Sensitizing Agents, Radiation
D002294 Carcinoma, Squamous Cell A carcinoma derived from stratified SQUAMOUS EPITHELIAL CELLS. It may also occur in sites where glandular or columnar epithelium is normally present. (From Stedman, 25th ed) Carcinoma, Epidermoid,Carcinoma, Planocellular,Carcinoma, Squamous,Squamous Cell Carcinoma,Carcinomas, Epidermoid,Carcinomas, Planocellular,Carcinomas, Squamous,Carcinomas, Squamous Cell,Epidermoid Carcinoma,Epidermoid Carcinomas,Planocellular Carcinoma,Planocellular Carcinomas,Squamous Carcinoma,Squamous Carcinomas,Squamous Cell Carcinomas
D006258 Head and Neck Neoplasms Soft tissue tumors or cancer arising from the mucosal surfaces of the LIP; oral cavity; PHARYNX; LARYNX; and cervical esophagus. Other sites included are the NOSE and PARANASAL SINUSES; SALIVARY GLANDS; THYROID GLAND and PARATHYROID GLANDS; and MELANOMA and non-melanoma skin cancers of the head and neck. (from Holland et al., Cancer Medicine, 4th ed, p1651) Cancer of Head and Neck,Head Cancer,Head Neoplasm,Head and Neck Cancer,Head and Neck Neoplasm,Neck Cancer,Neck Neoplasm,Neck Neoplasms,Neoplasms, Upper Aerodigestive Tract,UADT Neoplasm,Upper Aerodigestive Tract Neoplasm,Upper Aerodigestive Tract Neoplasms,Cancer of Head,Cancer of Neck,Cancer of the Head,Cancer of the Head and Neck,Cancer of the Neck,Head Neoplasms,Head, Neck Neoplasms,Neoplasms, Head,Neoplasms, Head and Neck,Neoplasms, Neck,UADT Neoplasms,Cancer, Head,Cancer, Neck,Cancers, Head,Cancers, Neck,Head Cancers,Neck Cancers,Neoplasm, Head,Neoplasm, Neck,Neoplasm, UADT,Neoplasms, UADT
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071877 Checkpoint Kinase 1 A serine/threonine-specific protein kinase which is encoded by the CHEK1 gene in humans. Checkpoint kinase 1 (also known as Chk1) coordinates DNA damage response and cell cycle checkpoint response. Under these conditions, activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death, to prevent damaged cells from progressing through the cell cycle. Checkpoint-1 Kinase,Chk1 Kinase,Chk1 Protein Kinase,Protein Kinase, Chk1
D000077195 Squamous Cell Carcinoma of Head and Neck The most common type of head and neck carcinoma that originates from cells on the surface of the NASAL CAVITY; MOUTH; PARANASAL SINUSES, SALIVARY GLANDS, and LARYNX. Mutations in TNFRSF10B, PTEN, and ING1 genes are associated with this cancer. HNSCC,Head And Neck Squamous Cell Carcinomas,Hypopharyngeal Squamous Cell Carcinoma,Laryngeal Squamous Cell Carcinoma,Oral Cavity Squamous Cell Carcinoma,Oral Squamous Cell Carcinoma,Oral Squamous Cell Carcinomas,Oral Tongue Squamous Cell Carcinoma,Oropharyngeal Squamous Cell Carcinoma,Squamous Cell Carcinoma of Larynx,Squamous Cell Carcinoma of the Larynx,Squamous Cell Carcinoma of the Mouth,Squamous Cell Carcinoma of the Nasal Cavity,Carcinoma, Squamous Cell of Head and Neck,Head and Neck Squamous Cell Carcinoma,Squamous Cell Carcinoma of the Head and Neck,Squamous Cell Carcinoma, Head And Neck
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D059565 G2 Phase Cell Cycle Checkpoints CELL CYCLE regulatory signaling systems that are triggered by DNA DAMAGE or lack of nutrients during G2 PHASE. When triggered they restrain cells transitioning from G2 phase to M PHASE. Antephase Checkpoint,G2 Cell Cycle Arrest,G2 Cell Cycle Checkpoints,G2 Cell Cycle Control,G2 Phase Checkpoints,G2 Restriction Point,G2-M Cell Cycle Checkpoint,Antephase Checkpoints,Checkpoint, Antephase,Checkpoint, G2 Phase,Checkpoints, Antephase,Checkpoints, G2 Phase,G2 M Cell Cycle Checkpoint,G2 Phase Checkpoint,G2 Restriction Points,Restriction Point, G2,Restriction Points, G2

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