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Cellular and Molecular Biology

Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation

British Journal of Cancer volume 127, pages 811–823 (2022)Cite this article

Subjects

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.

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Fig. 1: Increased glucose metabolism fuels trastuzumab resistance in trastuzumab-resistant HER2 + gastric cancer.
Fig. 2: Upregulation of PFKFB3 contributes to the resistance of gastric cancer cells to trastuzumab.
Fig. 3: PFKFB3 inhibition promotes tumour vessel normalisation and inhibits trastuzumab resistance.
Fig. 4: PFKFB3 mediates tumour vessel normalisation by promoting CXCL8 transcription and secretion in HER2+ gastric cancer.
Fig. 5: PFKFB3 promotes the transcription and secretion of CXCL8 by phosphorylating the S1151 site of ERBB2.
Fig. 6: PFKFB3 promotes the CXCL8 expression by activating the phosphorylation of ERBB2 S1151/PI3K/AKT/ NFκB p65 signal axis.

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Data availability

Data are available from the corresponding author upon reasonable request.

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Acknowledgements

We gratefully acknowledge Prof. Lin Shen (Department of Gastrointestinal Oncology, Peking University Cancer Hospital, Beijing, China) for providing HER2-positive gastric cancer PDX models.

Funding

This work was supported by the Natural Science Foundation of Guangdong Province (2019A1515010641, 2021A1515011721, 2022A1515010657), the Presidential Foundation of Nanfang Hospital, Southern Medical University (2018B002, 2018B016), the National Natural Science Foundation of China (No. 82003289, 81872013), the Guangdong Provincial Major Talents Project (No. 2019JC05Y361) and the Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer (2020B121201004).

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Author notes

  1. These authors contributed equally: Xingxing Yao, Zhanke He.

Authors and Affiliations

  1. Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, China

    Xingxing Yao, Zhanke He, Penghao Zhang, Chuyang Sui, Xiangqian Deng, Guoxin Li & Jiaolong Shi

  2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases & Department of Radiation Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China

    Caolitao Qin

  3. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Yuxin Fang

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Contributions

Contributors YXX and SJL designed the research. YXX, SJL, HZK, DXQ, ZPH and SCY performed experiments and acquisition of data. QCLT and FYX analysed and interpreted data. YXX and SJL wrote the paper. QCLT and Guoxin Li critically reviewed the manuscript. SJL and YXX supervised the project. All the work reported in the paper has been performed by the authors, unless clearly specified in the text. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Guoxin Li or Jiaolong Shi.

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This study was approved by the Medical Ethics Committee of Southern Medical University Nanfang Hospital. All protocols involving animals in the present study were approved by the laboratory animal ethics committee of Southern Medical University Nanfang Hospital. All the animal experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publications Nos. 80-23, revised 1996) and the institutional ethical guidelines for animal experiments.

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Yao, X., He, Z., Qin, C. et al. Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation. Br J Cancer 127, 811–823 (2022). https://doi.org/10.1038/s41416-022-01834-2

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