Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors

Koji Ando, Yara Hamade Tohme, Adithi Srinivasiah, Julian Taylor-Parker, Yevgeniya Harrington, Ankur K. Shah, Eiji Oki, Mohan Brahmandam, Ajit K. Bharti

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)549-561
Number of pages13
JournalJournal of Histochemistry and Cytochemistry
Volume66
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

All Science Journal Classification (ASJC) codes

  • Anatomy
  • Histology

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    Ando, K., Tohme, Y. H., Srinivasiah, A., Taylor-Parker, J., Harrington, Y., Shah, A. K., Oki, E., Brahmandam, M., & Bharti, A. K. (2018). Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors. Journal of Histochemistry and Cytochemistry, 66(8), 549-561. https://doi.org/10.1369/0022155418766503