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Inhibition of Aurora B kinase (AURKB) enhances the effectiveness of 5-fluorouracil chemotherapy against colorectal cancer cells.
Shah, Esha T; Molloy, Christopher; Gough, Madeline; Kryza, Thomas; Samuel, Selwin G; Tucker, Amos; Bhatia, Maneet; Ferguson, Genevieve; Heyman, Rebecca; Vora, Shivam; Monkman, James; Bolderson, Emma; Kulasinghe, Arutha; He, Yaowu; Gabrielli, Brian; Hooper, John D; Richard, Derek J; O'Byrne, Kenneth J; Adams, Mark N.
Afiliação
  • Shah ET; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Molloy C; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Gough M; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Kryza T; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Samuel SG; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Tucker A; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Bhatia M; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Ferguson G; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Heyman R; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Vora S; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Monkman J; Frazer Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Bolderson E; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Kulasinghe A; Frazer Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • He Y; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Gabrielli B; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Hooper JD; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Richard DJ; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • O'Byrne KJ; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
  • Adams MN; Cancer Services, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD, 4102, Australia.
Br J Cancer ; 130(7): 1196-1205, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38287178
ABSTRACT

BACKGROUND:

5-Fluorouracil (5-FU) remains a core component of systemic therapy for colorectal cancer (CRC). However, response rates remain low, and development of therapy resistance is a primary issue. Combinatorial strategies employing a second agent to augment the therapeutic effect of chemotherapy is predicted to reduce the incidence of treatment resistance and increase the durability of response to therapy.

METHODS:

Here, we employed quantitative proteomics approaches to identify novel druggable proteins and molecular pathways that are deregulated in response to 5-FU, which might serve as targets to improve sensitivity to chemotherapy. Drug combinations were evaluated using 2D and 3D CRC cell line models and an ex vivo culture model of a patient-derived tumour.

RESULTS:

Quantitative proteomics identified upregulation of the mitosis-associated protein Aurora B (AURKB), within a network of upregulated proteins, in response to a 24 h 5-FU treatment. In CRC cell lines, AURKB inhibition with the dihydrogen phosphate prodrug AZD1152, markedly improved the potency of 5-FU in 2D and 3D in vitro CRC models. Sequential treatment with 5-FU then AZD1152 also enhanced the response of a patient-derived CRC cells to 5-FU in ex vivo cultures.

CONCLUSIONS:

AURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Organofosfatos / Quinazolinas / Neoplasias Colorretais / Fluoruracila Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Organofosfatos / Quinazolinas / Neoplasias Colorretais / Fluoruracila Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article