Inhibition of ATR-dependent feedback activation of Chk1 sensitises cancer cells to Chk1 inhibitor monotherapy
作者： Andrew J. Massey
DOI: 10.1016/J.CANLET.2016.09.024
关键词:
摘要: The Chk1 and ATR kinases are critical mediators of the DNA damage response pathway help protect cancer cells from endogenous oncogene induced replication stress. Inhibitors both currently being evaluated in clinical trials. inhibition with V158411 increases activates ATR, ATM DNA-PKcs dependent pathways. Inhibiting and/or has potential to increase therapeutic activity inhibitors. but not or potentiated cytotoxicity p53 mutant wild type human cell lines. This increased correlated nuclear stress a dose time manner. γH2AX induction following protected caspase-dependent apoptosis. Inhibition inhibitor death independently caspase activation. effect DNA-PK on was concentration inhibitor. via abrogation ATR-dependent feedback activation by generated study suggests that combining an lower threshold which induces stress, tumour wide range types may be useful approach.
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