| Autor: |
Ando, Koji, Tohme, Yara Hamade, Srinivasiah, Adithi, Taylor-Parker, Julian, Harrington, Yevgeniya, Shah, Ankur K., Oki, Eiji, Brahmandam, Mohan, Bharti, Ajit K. |
| Předmět: |
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| Zdroj: |
Journal of Histochemistry & Cytochemistry; Aug2018, Vol. 66 Issue 8, p549-561, 13p |
| Abstrakt: |
Phosphorylation is the most extensively studied posttranslational modification of proteins. There are approximately 500 kinases known in the human genome. The kinase-activated pathways regulate almost every aspect of cell function and a deregulated kinase cascade leads to impaired cellular function. Impaired regulation of several kinase cascades, including the epidermal growth factor receptor (EGFR) pathway, leading to tumor pathogenesis, is well documented. Thus, a phosphospecific test with prognostic or predictive value was expected in oncology. However, no phosphospecific IHC test is used in oncology clinics. Human topoisomerase I (topoI) inhibitors, camptothecin and its analogues (CPT), are used extensively to treat various solid tumors. Depending on tumor type, the response rate is only 13–32%. We have demonstrated that the deregulated kinase cascade is at the core of CPT resistance. DNA-PKcs, a kinase central to the DNA–double-strand break (DSB) response pathway, phosphorylates topoI at serine 10 (topoI-pS10), and cells with higher basal levels of topoI-pS10 degrade topoI rapidly and are resistant to this class of drug. The higher basal level of topoI phosphorylation is due to continual activation of DNA-PKcs, and one potential mechanism of this pathway activation is failure of upstream effector phosphatases such as phosphatase and tensin homolog (PTEN). Based on this understanding, we have developed an IHC-based test (P-topoIDx) that can stratify the responder and non-responder patient population. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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