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- Title
Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation.
- Authors
Yao, Xingxing; He, Zhanke; Qin, Caolitao; Zhang, Penghao; Sui, Chuyang; Deng, Xiangqian; Fang, Yuxin; Li, Guoxin; Shi, Jiaolong
- Abstract
Background: Multiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics. Methods: We established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings. Results: The 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway. Conclusions: Our current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.
- Publication
British Journal of Cancer, 2022, Vol 127, Issue 5, p811
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/s41416-022-01834-2