T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics

‘Targeted’ or ‘biological’ cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues,...

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Vydané v:Cell death & disease Ročník 9; číslo 11; s. 1089 - 10
Hlavní autori: Herbert, Katharine J., Ashton, Thomas M., Prevo, Remko, Pirovano, Giacomo, Higgins, Geoff S.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 24.10.2018
Springer Nature B.V
Predmet:
Animals
Antibodies
Biochemistry
Biomarkers, Tumor - antagonists & inhibitors
Biomarkers, Tumor - metabolism
Biomedical and Life Sciences
Cancer
Cancer therapies
Cell Biology
Cell Culture
Cell cycle
Cell Line, Tumor
Clinical trials
Disease Models, Animal
Drug Discovery - methods
Gene expression
Humans
Immunology
Indolizines - pharmacology
Indolizines - therapeutic use
Kinases
Life Sciences
Mice
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - metabolism
Molecular Targeted Therapy
Neoplasms - drug therapy
Neoplasms - metabolism
Protein kinase
Quinolones - pharmacology
Quinolones - therapeutic use
Quinoxalines - pharmacology
Quinoxalines - therapeutic use
Review
Review Article
Thiophenes - pharmacology
Thiophenes - therapeutic use
Toxicity
Treatment Outcome
Treatment resistance
Tumors
ISSN:2041-4889, 2041-4889
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Abstract ‘Targeted’ or ‘biological’ cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.
AbstractList ‘Targeted’ or ‘biological’ cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.
'Targeted' or 'biological' cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.'Targeted' or 'biological' cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.
ArticleNumber 1089
Author Herbert, Katharine J.
Higgins, Geoff S.
Prevo, Remko
Ashton, Thomas M.
Pirovano, Giacomo
Author_xml – sequence: 1
  givenname: Katharine J.
  orcidid: 0000-0001-9437-0253
  surname: Herbert
  fullname: Herbert, Katharine J.
  email: katharine.herbert@oncology.ox.ac.uk
  organization: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building
– sequence: 2
  givenname: Thomas M.
  surname: Ashton
  fullname: Ashton, Thomas M.
  organization: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building
– sequence: 3
  givenname: Remko
  surname: Prevo
  fullname: Prevo, Remko
  organization: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building
– sequence: 4
  givenname: Giacomo
  surname: Pirovano
  fullname: Pirovano, Giacomo
  organization: Department of Radiology, Memorial Sloan-Kettering Cancer Center
– sequence: 5
  givenname: Geoff S.
  surname: Higgins
  fullname: Higgins, Geoff S.
  organization: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30356039$$D View this record in MEDLINE/PubMed
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Snippet ‘Targeted’ or ‘biological’ cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour...
'Targeted' or 'biological' cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour...
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SubjectTerms Animals
Antibodies
Biochemistry
Biomarkers, Tumor - antagonists & inhibitors
Biomarkers, Tumor - metabolism
Biomedical and Life Sciences
Cancer
Cancer therapies
Cell Biology
Cell Culture
Cell cycle
Cell Line, Tumor
Clinical trials
Disease Models, Animal
Drug Discovery - methods
Gene expression
Humans
Immunology
Indolizines - pharmacology
Indolizines - therapeutic use
Kinases
Life Sciences
Mice
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - metabolism
Molecular Targeted Therapy
Neoplasms - drug therapy
Neoplasms - metabolism
Protein kinase
Quinolones - pharmacology
Quinolones - therapeutic use
Quinoxalines - pharmacology
Quinoxalines - therapeutic use
Review
Review Article
Thiophenes - pharmacology
Thiophenes - therapeutic use
Toxicity
Treatment Outcome
Treatment resistance
Tumors
Title T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics
URI https://link.springer.com/article/10.1038/s41419-018-1131-7
https://www.ncbi.nlm.nih.gov/pubmed/30356039
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Volume 9
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