Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation
Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation
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DOI：
10.1038/s41416-022-01834-2
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发表时间：
2022-05
影响因子：
8.8
通讯作者：
Xingxing Yao;Zhanke He;Caolitao Qin;Penghao Zhang;Chuyang Sui;Xiangqian Deng;Yuxin Fang;Guoxin Li
中科院分区：
文献类型：
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作者：
Xingxing Yao;Zhanke He;Caolitao Qin;Penghao Zhang;Chuyang Sui;Xiangqian Deng;Yuxin Fang;Guoxin Li
BackgroundMultiple 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.MethodsWe established trastuzumab-resistant cells and patient-derived xenografts model to measure metabolic levels and vascular density and shape.使用HER 2阳性GC患者样本确定临床意义。我们还测量了蛋白质表达和磷酸化修饰，以确定与抗性相关的那些改变。在体内研究结合抑制剂PFKFB 3与曲妥珠单抗证实了在体外findings.ResultsThe 6-phosphofructo-2-kinase（PFKFB 3）介导的曲妥珠单抗耐药途径在HER 2阳性GC通过激活糖酵解途径。我们还发现，在曲妥珠单抗耐药过程中，肿瘤中的血管是混乱和不稳定的。在患者来源的异种移植模型中，抑制PFKFB 3显著减少了肿瘤增殖并促进了血管正常化。机制上，PFKFB 3促进CXCL 8分泌到肿瘤微环境中，并磷酸化ERBB 2的Ser 1151，通过激活PI 3 K/AKT/NFκB p65通路增强CXCL 8的转录。结论我们目前的研究发现，PFKFB 3抑制剂可能是克服HER 2 - 1患者辅助治疗耐药的有效工具。通过使肿瘤血管正常化来重塑微环境是克服曲妥珠单抗耐药性的新策略。
BackgroundMultiple 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.