LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms
- 1 September 2015
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 14 (9), 2004-2013
- https://doi.org/10.1158/1535-7163.mct-14-1037
Abstract
CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe. Mol Cancer Ther; 14(9); 2004–13. ©2015 AACR.Keywords
Other Versions
This publication has 36 references indexed in Scilit:
- CHEK again: Revisiting the development of CHK1 inhibitors for cancer therapyPharmacology & Therapeutics, 2014
- The cancer therapeutic potential of Chk1 inhibitors: how mechanistic studies impact on clinical trial designBritish Journal of Clinical Pharmacology, 2013
- DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical BiologyCell Chemical Biology, 2013
- Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung CancerThe Cancer Journal, 2013
- Roles of Chk1 in cell biology and cancer therapyInternational Journal of Cancer, 2013
- Small molecule drugs – optimizing DNA damaging agent-based therapeuticsCurrent Opinion in Pharmacology, 2012
- Replication fork dynamics and the DNA damage responseBiochemical Journal, 2012
- Checkpoint control and cancerOncogene, 2011
- The p53 tumor suppressor participates in multiple cell cycle checkpointsJournal of Cellular Physiology, 2006
- Inhibition of Human Chk1 Causes Increased Initiation of DNA Replication, Phosphorylation of ATR Targets, and DNA BreakageMolecular and Cellular Biology, 2005