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 language | English |
|---|---|
| Pages (from-to) | 549-561 |
| Number of pages | 13 |
| Journal | Journal of Histochemistry and Cytochemistry |
| Volume | 66 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2018 |
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All Science Journal Classification (ASJC) codes
- Anatomy
- Histology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors
AU - Ando, Koji
AU - Tohme, Yara Hamade
AU - Srinivasiah, Adithi
AU - Taylor-Parker, Julian
AU - Harrington, Yevgeniya
AU - Shah, Ankur K.
AU - Oki, Eiji
AU - Brahmandam, Mohan
AU - Bharti, Ajit K.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045046062&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045046062&partnerID=8YFLogxK
U2 - 10.1369/0022155418766503
DO - 10.1369/0022155418766503
M3 - Article
C2 - 29587004
AN - SCOPUS:85045046062
VL - 66
SP - 549
EP - 561
JO - Journal of Histochemistry and Cytochemistry
JF - Journal of Histochemistry and Cytochemistry
SN - 0022-1554
IS - 8
ER -