An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation.
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<h4>Purpose</h4>Chk1 inhibition increases cell sensitivity to both chemotherapy and radiotherapy in several tumour types and is, therefore, a promising anti-cancer approach. Although several Chk1 inhibitors have been developed, their clinical progress has been hampered by low bioavailability and off-target toxicities.<h4>Materials and methods</h4>We characterized the radiosensitizing activity of CCT244747, the first orally bioavailable Chk1 inhibitor. We used a panel of bladder and head and neck cancer cell lines and monitored the effect of combining CCT244747 with radiation both in in vitro and in vivo models.<h4>Results</h4>CCT244747 sensitized cancer cell lines to radiation in vitro and resulted in a growth delay in cancer xenograft models associated with a survival benefit. Radiosensitization was elicited by abrogation of the radiation-induced G2 arrest and premature entry into mitosis.<h4>Conclusions</h4>CCT244747 is a potent and specific Chk1 inhibitor that can be administered orally. It radiosensitizes tumour cell lines and represents a new therapy for clinical application in combination with radiotherapy.
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Cell Line, Tumor
Head and Neck Neoplasms
Urinary Bladder Neoplasms
G2 Phase Cell Cycle Checkpoints
Checkpoint Kinase 1
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Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2017, 122 (3), pp. 470 - 475