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.
Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
Br J Cancer. 2024 Apr;130(7):1196-1205. doi: 10.1038/s41416-024-02584-z. Epub 2024 Jan 29.
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.
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.
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.
AURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.
5-氟尿嘧啶（5-FU）仍然是结直肠癌（CRC）系统治疗的核心组成部分。然而，反应率仍然较低，治疗耐药性的发展是一个主要问题。联合使用第二种药物增强化疗治疗效果的组合策略，预计可以降低治疗耐药性的发生率，并提高对治疗的反应持久性。
在这里，我们采用定量蛋白质组学方法来鉴定新型可用药蛋白和分子途径，这些蛋白和分子途径在对 5-FU 的反应中被下调，它们可能成为提高化疗敏感性的靶点。使用二维和三维 CRC 细胞系模型以及患者来源的肿瘤的体外培养模型来评估药物组合。
定量蛋白质组学鉴定出在对 24 小时 5-FU 处理的反应中，有丝分裂相关蛋白 Aurora B（AURKB）在一组上调蛋白的网络中上调。在 CRC 细胞系中，用二氢磷酸盐前药 AZD1152 抑制 AURKB，显著提高了二维和三维体外 CRC 模型中 5-FU 的效力。5-FU 然后再用 AZD1152 序贯治疗也增强了患者来源的 CRC 细胞对体外培养物中 5-FU 的反应。
AURKB 抑制可能是增强 CRC 中 5-FU 化疗有效性的合理方法。
