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

Author:

Ando Koji12,Tohme Yara Hamade1,Srinivasiah Adithi1,Taylor-Parker Julian1,Harrington Yevgeniya1,Shah Ankur K.1,Oki Eiji2,Brahmandam Mohan3,Bharti Ajit K.1

Affiliation:

1. Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

2. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

3. Monoclonal Antibody Core Facility, Dana-Farber Cancer Institute, Boston, Massachusetts

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.

Funder

Boston University Medical School

Publisher

SAGE Publications

Subject

Histology,Anatomy

Reference16 articles.

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