Dovitinib induces mitotic defects and activates the G2 DNA damage checkpoint.
Dovitinib (TKI258; formerly CHIR-258) is an orally bioavailable inhibitor of multiple receptor tyrosine kinases. Interestingly, Dovitinib triggered a G2 /M arrest in cancer cell lines from diverse origins including HeLa, nasopharyngeal carcinoma, and hepatocellular carcinoma. Single-cell analysis revealed that Dovitinib promoted a delay in mitotic exit in a subset of cells, causing the cells to undergo mitotic slippage. Higher concentrations of Dovitinib induced a G2 arrest similar to the G2 DNA damage checkpoint. In support of this, DNA damage was triggered by Dovitinib as revealed by γ-H2AX and comet assays. The mitotic kinase CDK1 was found to be inactivated by phosphorylation in the presence of Dovitinib. Furthermore, the G2 arrest could be overcome by abrogation of the G2 DNA damage checkpoint using small molecule inhibitors of CHK1 and WEE1. Finally, Dovitinib-mediated G2 cell cycle arrest and subsequent cell death could be promoted after DNA damage repair was disrupted by inhibitors of poly(ADP-ribose) polymerases. These results are consistent with the recent finding that Dovitinib can also target topoisomerases. Collectively, these results suggest additional directions for use of Dovitinib, in particular with agents that target the DNA damage checkpoint.
Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Wing Yu
WY
Man
Joyce P Y
JP
Mak
Randy Y C
RY
Poon
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology*; D059010:Single-Cell Analysis
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; D011065:Poly(ADP-ribose) Polymerases; D016203:CDC2 Protein Kinase; C531550:olaparib
Checkpoint; DNA damage; TKI258; mitosis