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

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Topoisomerase I Inhibitors
Type I DNA Topoisomerase
Phosphotransferases
Biomarkers
Phosphoric Monoester Hydrolases
Phosphorylation
Camptothecin
Neoplasms
DNA
Human Genome
Post Translational Protein Processing
Epidermal Growth Factor Receptor
Serine
Pharmaceutical Preparations
Population

All Science Journal Classification (ASJC) codes

  • Anatomy
  • Histology

Cite this

Ando, K., Tohme, Y. H., Srinivasiah, A., Taylor-Parker, J., Harrington, Y., Shah, A. K., ... 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

Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors. / Ando, Koji; Tohme, Yara Hamade; Srinivasiah, Adithi; Taylor-Parker, Julian; Harrington, Yevgeniya; Shah, Ankur K.; Oki, Eiji; Brahmandam, Mohan; Bharti, Ajit K.

In: Journal of Histochemistry and Cytochemistry, Vol. 66, No. 8, 01.08.2018, p. 549-561.

Research output: Contribution to journalArticle

Ando, K, Tohme, YH, Srinivasiah, A, Taylor-Parker, J, Harrington, Y, Shah, AK, Oki, E, Brahmandam, M & Bharti, AK 2018, 'Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors', Journal of Histochemistry and Cytochemistry, vol. 66, no. 8, pp. 549-561. https://doi.org/10.1369/0022155418766503
Ando, Koji ; Tohme, Yara Hamade ; Srinivasiah, Adithi ; Taylor-Parker, Julian ; Harrington, Yevgeniya ; Shah, Ankur K. ; Oki, Eiji ; Brahmandam, Mohan ; Bharti, Ajit K. / Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors. In: Journal of Histochemistry and Cytochemistry. 2018 ; Vol. 66, No. 8. pp. 549-561.
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