An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation

Radhika N Patel, Holly E. Barker, Joan N Kyula, Martin McLaughlin, Magnus T. Dillon, Ulrike Schick, Hind Hafsi, Alan Thompson, Vincent Khoo, Kevin J Harrington, Shane Zaidi

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)470-475
Number of pages6
JournalRadiotherapy and Oncology
Volume122
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017
Externally publishedYes

Keywords

  • Bladder cancer
  • Chk1 inhibition
  • Head and neck cancer
  • Radiation
  • Radiosensitization

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