PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from
Upadhyayula S Srinivas1, Norbert S C Tay1, Patrick Jaynes1
1Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore.
Abstract:
Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.
Insights
Tumor suppressor ARID1A deficiency confers sensitivity to PLK1 inhibitors by disrupting mitochondrial function. This discovery reveals a novel therapeutic strategy for refractory cancers, utilizing PLK1 inhibitors with a patient selection marker based on ARID1A loss.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Pololike kinase 1 (PLK1) inhibitors show promise in refractory cancers, but lack predictive biomarkers for patient selection.
- Overexpression of PLK1 does not reliably predict sensitivity to PLK1 inhibitors.
- Identifying specific genetic alterations that sensitize tumors to PLK1 inhibition is crucial for clinical development.
Purpose of the Study:
- To identify biomarkers for patient selection in PLK1 inhibitor therapy.
- To investigate the mechanism underlying PLK1 inhibitor sensitivity in specific cancer contexts.
- To explore novel therapeutic strategies targeting PLK1 in cancer.
Main Methods:
- High-throughput chemical screening to identify drug-sensitive cell lines.
- Whole-genome CRISPR screening to uncover genetic dependencies.
- Expansion microscopy and biochemical fractionation to study protein localization.
- Assessment of mitochondrial function, including oxygen consumption and ATP production.
- Quantitative microscopy assay for ARID1A protein loss detection.
Main Results:
- Cells deficient in the tumor suppressor ARID1A exhibit high sensitivity to PLK1 inhibitors.
- This sensitivity is dependent on the mitochondrial translation machinery, not canonical cell cycle roles of PLK1.
- ARID1A-deficient cells display aberrant mitochondrial biogenesis and uncoupled oxidative phosphorylation.
- PLK1 inhibition in ARID1A-deficient cells leads to mitochondrial membrane depolarization and apoptosis.
- Loss of ARID1A protein can be quantified using a novel microscopy assay.
Conclusions:
- ARID1A deficiency represents a novel predictive biomarker for PLK1 inhibitor therapy.
- PLK1 has an uncharacterized interphase role in maintaining mitochondrial fitness under metabolic stress.
- Targeting PLK1 in ARID1A-deficient cancers offers a promising therapeutic strategy.
- A quantitative assay for ARID1A loss can aid in patient selection for clinical trials.
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