An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation. Issue 3 (March 2017)

• Record Type: Journal Article
• Authors: Patel, Radhika; Barker, Holly E.; Kyula, Joan; McLaughlin, Martin; Dillon, Magnus T.; Schick, Ulrike; Hafsi, Hind; Thompson, Alan; Khoo, Vincent; Harrington, Kevin; Zaidi, Shane
• Is Part Of: Radiotherapy and oncology. Volume 122:Issue 3(2017:Mar.)
• Page Start: 470
• Page End: 475
• Publication Date: 2017-03
• Subjects: Radiosensitization -- Bladder cancer -- Head and neck cancer -- Radiation -- Chk1 inhibition; Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2016.12.026
• Languages: English
• ISSNs: 0167-8140

Abstract

Abstract: Purpose: 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. Materials and methods: 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. Results: 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. Conclusions: 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.