Suppression of Chromosome Instability (CIN) to Enhance Chemosensitivity of Ovarian Tumor Cells by Modulating the Aurora B Pathway at Kinetochores.

摘要

Aneuploidy is a hallmark of virtually all ovarian cancer cells and is thus indicative of chromosome instability (CIN). CIN may be a preprogrammed strategy of cancer cells to generate enormous genetic and biochemical diversity in a single cell division. CIN therefore allows cancer cells to rapidly evolve and survive suboptimal growth conditions that include drug treatments. The molecular basis of CIN is unclear but we discovered that Aurora B kinase is unable to phosphorylate proteins that are critical for preventing CIN. Restoring Aurora B function can reduce chromosome missegregation in ovarian cancer cells. This strategy should limit their ability to evolve and thus should increase chemosensitivity. We conducted a screen of clinically relevant kinase inhibitors to identify compounds that exhibits off-target effects on the DNA damage checkpoint. Most chemotherapies damage DNA which arrests cells to provide time to repair the damage. Crippling the checkpoint is known to enhance drug sensitivity because cells are forced to enter mitosis with damaged DNA. We identified Bostunib, an FDA approved src/abl inhibitor, as a new checkpoint inhibitor. As compounds specifically designed to inhibit Chk1 were toxic in patients, Bosutinib may provide the first clinically tolerable chemosensitizing agent that targets the DNA damage checkpoint.