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Insulin receptor expression to predict resistance to axitinib and elucidation of the underlying molecular mechanism in metastatic renal cell carcinoma

British Journal of Cancer volume 129, pages 521–530 (2023)Cite this article

Subjects

Abstract

Background

The study aimed to examine the significance of insulin receptor (INSR) expression in predicting resistance to axitinib in clear cell renal cell carcinoma (ccRCC).

Methods

Clinicopathological data were collected from 36 consecutive patients with metastatic RCC who received axitinib. Thirty-three primary tumours were obtained for immunohistochemistry. Patient-derived xenograft (PDX) models were created by transplanting primary tumours into immunodeficient mice, establishing axitinib-resistant PDX models. RCC cell lines were co-cultured with human renal glomerular endothelial cells (HGECs) treated with siRNA of INSR (HGEC-siINSR). Gene expression alteration was analysed using microarray.

Results

The patients with low INSR expression who received axitinib had a poorer outcome. Multivariate analysis showed that INSR expression was the independent predictor of progression-free survival. INSR expression decreased in axitinib-resistant PDX tumours. RCC cell lines showed upregulated interferon responses and highly increased interferon-β levels by co-culturing with HGEC-siINSR. HGECs showed decreased INSR and increased interferon-β after axitinib administration. RCC cell lines co-cultured with HGEC-siINSR showed high programmed death-ligand 1 (PD-L1) expression, which increased after interferon-β administration.

Conclusions

Decreased INSR in RCC could be a biomarker to predict axitinib resistance. Regarding the resistant mechanism, vascular endothelial cells with decreased INSR in RCC may secrete interferon-β and induce PD-L1.

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Fig. 1: Survival of patients with RCC according to INSR expression.
Fig. 2: INSR expression in axitinib-resistant or -sensitve PDX tumours.
Fig. 3: Alteration of gene expression in RCC cell lines cocultured with HGECs with down-regulated INSR.
Fig. 4: Interferon-β and PD-L1 expressions associated with HGECs with down-regulated INSR or axitinib administration.

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Data availability

The data sets analysed during this study are available from the corresponding author upon reasonable request. Publicly available data sets were extracted from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) and cBioportal (https://www.cbioportal.org/).

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Funding

Funding was provided by a research grant from Novartis Pharma (grant numbers not applicable) and MSD (grant numbers not applicable).

Author information

Authors and Affiliations

  1. Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Masayuki Takahashi, Kei Daizumoto, Tomoya Fukawa, Yayoi Fukuhara, Minoru Kowada, Tsogt-Ochir Dondoo, Yutaro Sasaki, Ryotaro Tomida, Yoshiteru Ueno, Megumi Tsuda, Yoshito Kusuhara, Kunihisa Yamaguchi, Yasuyo Yamamoto & Hiroomi Kanayama

  2. Division of Pathology, Tokushima University Hospital, Tokushima, Japan

    Yoshimi Bando & Hisanori Uehara

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  1. Masayuki Takahashi
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Contributions

M Takahashi planned the study, collected the patients’ data and tumour samples, obtained informed consent from the patients, analysed the results, and wrote the manuscript. KD planned and performed the experiments, collected tumour samples, obtained informed consent, analysed the results, and helped write the manuscript. TF planned the experiments, collected tumour samples, obtained informed consent, and helped write the manuscript. YF performed the experiments and helped write the manuscript. YB and HU performed immunohistochemical staining and evaluation. MK performed the bioinformatic analysis for the microarray data. T-OD performed immunohistochemical staining and animal experiments. YS, RT, YU, M Tsuda, YK, KY, and YY collected tumour samples, obtained informed consents, and helped write the manuscript. HK supervised the study as a whole and helped write the manuscript.

Corresponding author

Correspondence to Masayuki Takahashi.

Ethics declarations

Competing interests

M Takahashi received honoraria from Pfizer Inc. and a research grant from Novartis Pharma and MSD. HK received honoraria from Pfizer Inc. Other authors have no conflict of interest.

Ethics approval and consent to participate

The study was approved by the ethical review board of Tokushima University Hospital (permission number 709) and conducted according to the ethical standards of the Declaration of Helsinki. The ethical review board of Tokushima University Hospital (permission number: 1841) and the Institutional Animal Care and Use Committee (Permission number: T2019-56) of Tokushima University approved the animal experiments. All of the animal experiments were performed according to guidelines of the animal facility at the University of Tokushima and conform to Fundamental Guidelines for Proper Conduct of Animal Experiments and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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Written informed consent for data usage and publication was obtained from all patients.

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Takahashi, M., Daizumoto, K., Fukawa, T. et al. Insulin receptor expression to predict resistance to axitinib and elucidation of the underlying molecular mechanism in metastatic renal cell carcinoma. Br J Cancer 129, 521–530 (2023). https://doi.org/10.1038/s41416-023-02325-8

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  • DOI: https://doi.org/10.1038/s41416-023-02325-8

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