Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Aurora kinases are a conserved family of serine threonine ki

    2022-10-31

    Aurora kinases are a conserved family of serine/threonine kinases that are important for the transition through mitosis and amplification and overexpression of Aurora kinases have been implicated in HO-3867 and transformation. Aurora B is located at the centromere and controls aspects of kinetochore stabilization, kinetochore-microtubule attachment, and chromosome segregation during mitosis [33]. Aurora A is located at centrosomes and spindle poles, and it functions in centrosome maturation and separation and in bipolar spindle assembly during mitosis. Aurora C functions similarly to Aurora B but during meiosis, and accordingly it is expressed only in the testis [24]. Aurora B inhibition in a wide range of solid tumors cancers led to an increase in cancer cell polyploidy, apoptosis, mitotic catastrophe, and decreased tumor size [[34], [35], [36]]. Inhibition of Aurora A results in abnormal mitotic spindles, defects in chromosomal segregation, and aneuploidy [24]. Few studies have addressed the role of Aurora kinases in HNSCC and CESC [20]. Expression of both Aurora A mRNA and protein in HNSCC and CESC tumors was higher than was their expression in normal tissues and correlated with advanced stage and worse outcome [20,37]. Aurora B expression was higher in oral squamous cell carcinoma than in normal epithelium and also correlated with nodal metastasis and poor differentiation [38]. Aurora B expression has not consistently correlated with stage and outcome in HNSCC and CESC [[39], [40], [41]]. Both Aurora B inhibition and Aurora A silencing induced apoptosis in HNSCC cell lines [41,42]. A kinase siRNA screen in CESC cell lines identified Aurora A and B as top hits that affected cell viability. Interestingly, PLK1 was also identified in this screen. Inhibition of Aurora A led to mitotic delay, polyploidy, and apoptosis in CESC cell lines in vitro and to decreased tumor size in vivo [23]. One cervical cancer patient had a partial response to an Aurora B inhibitor in a phase 1 study [43]. Despite the acceptable toxicity profile, the response rates of danusertib in solid tumor patients have been low [44], demonstrating the importance of biomarkers to enable patient selection. No biomarkers of sensitivity to Aurora kinase inhibition have been validated, but cell lines that overexpress MYC are more sensitive to Aurora B inhibition [[45], [46], [47]]. An Aurora A inhibitor was more effective in breast cancer cell lines lacking estrogen receptor and HER2 expression or with mutant TP53 [48]. Our study suggests that KMT2D mutations may be a suitable biomarker for patient selection since they correlate with sensitivity in our cell lines. The mechanism underlying this association is unknown and will be the focus of our future studies. KMT2D is a major H3K4 mono-methyl transferase that functions in cell type–specific gene expression [49]. Truncating mutations occur in many cancers including bladder cancer (23%), skin squamous carcinoma (17%), HNSCC (12%), CESC (9%), and lung SCC (11%) (cBioPortal 1/2/2018). Cells with KMT2D deficiency display transcriptional stress [50], and we speculate that when exposed to Aurora kinase inhibition, these cell lines are more likely to undergo mitotic catastrophe. Because KMT2D is a co-activator of TP53, another possible mechanism is that KMT2D deficient cancer cells are less able to engage p53-mediated arrest and more likely to accumulate DNA damage following Aurora kinase inhibition [51]. There were several limitations to our study. First, all of the drugs were tested at the same concentration range (0.01–3.6 μM). Drugs that are less potent but may still have a good therapeutic index may have been incorrectly labeled as ineffective. In addition, drugs were placed into classes on the basis of their primary targets, but drugs have multiple targets. Future studies will include analysis based on the specific target within the class and drug potency to address these two limitations. A third limitation is that this was an in vitro screen in established cell lines that does not account for effects on the tumor microenvironment. More extensive in vivo studies are planned. Although our HTDS included all the testable HPV-positive cell lines, only 20 of the 50 most common mutations were represented, and we may have missed important biomarkers that would have been revealed with a larger number of cell lines. Finally, all drugs have off-target effects, and it was not possible to confirm all of our findings with more specific molecular techniques.