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.
Subject(s)
Cell Cycle Proteins , DNA-Binding Proteins , Neoplasms , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins , Transcription Factors , Adenosine Triphosphate/metabolism , Apoptosis , Cell Cycle Proteins/genetics , Cell Line, Tumor , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Oxygen Consumption , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Polo-Like Kinase 1ABSTRACT
Positron emission tomography has emerged as an important diagnostic tool in the management of lung cancers. PET is sensitive in the detection of lung cancer, but FDG (2-deoxy-2-18fluro-D-glucose) is not tumor specific and may accumulate in a variety of non-malignant conditions occasionally giving false negative result. The addition of CT to PET improves specificity foremost, but also sensitivity in tumor imaging. Thus, PET/CT fusion images are a more accurate test than either of its individual components and are probably also better than side-by-side viewing of images from both modalities. PET/CT fusion images are useful in differentiating between malignant and benign disease, fibrosis and recurrence, staging and in changing patient management to a more appropriate therapy. With analysis and discussion, it appears that PET/ CT fusion images have the potential to dramatically improve our ability to manage the patients with lung cancer and is contributing to our understanding of cancer cell biology and in the development of new therapies.
