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However, PLK1 overexpression in cancer does not indicate drug tolerance, and the clinical development of PLK1 inhibitors has been hampered by a lack of a patient selection indicator. Cells deficient for the tumor suppressor ARID1A are extremely sensitive to PLK1 inhibition, according to a high-throughput chemical screen. PLK1 inhibitor sensitivity in ARID1A deficient cells has been found to be dependent on the mitochondrial translation machinery, according to a whole-genome CRISPR screen. PLK1 inhibition in ARID1A KO cells also increases oxygen consumption from ATP manufacture, despite subsequent membrane depolarization and apoptosis. These results, as well as a plan for therapeutic use of PLK1 inhibitors, highlight a new interphase role for PLK1 in maintaining mitochondrial health under metabolic strain. To summarize these results, we introduce a quantitative microscopy assay for determining ARID1A protein loss, which may be a novel patient selection tactic for cancer-related PLK1 inhibitors.
Source link: https://doi.org/10.1038/s41388-022-02219-8
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