Insulin receptor expression to predict resistance to axitinib and elucidation of the underlying molecular mechanism in metastatic renal cell carcinoma.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
11
08
2020
accepted:
13
06
2023
revised:
27
05
2023
pmc-release:
24
06
2024
medline:
7
8
2023
pubmed:
25
6
2023
entrez:
24
6
2023
Statut:
ppublish
Résumé
The study aimed to examine the significance of insulin receptor (INSR) expression in predicting resistance to axitinib in clear cell renal cell carcinoma (ccRCC). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37355721
doi: 10.1038/s41416-023-02325-8
pii: 10.1038/s41416-023-02325-8
pmc: PMC10403594
doi:
Substances chimiques
Axitinib
C9LVQ0YUXG
B7-H1 Antigen
0
Insulin
0
Receptor, Insulin
EC 2.7.10.1
Interferon-beta
77238-31-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
521-530Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
Références
J Clin Oncol. 2009 Jul 1;27(19):3225-34
pubmed: 19470934
N Engl J Med. 2015 Nov 5;373(19):1803-13
pubmed: 26406148
Urol Oncol. 2017 Sep;35(9):541.e15-541.e22
pubmed: 28623071
N Engl J Med. 2012 Mar 8;366(10):883-892
pubmed: 22397650
Nat Med. 2003 May;9(5):562-7
pubmed: 12704383
N Engl J Med. 2007 Jan 11;356(2):115-24
pubmed: 17215529
Lancet Oncol. 2013 Feb;14(2):141-8
pubmed: 23312463
Cancer Res. 2006 Apr 1;66(7):3381-5
pubmed: 16585157
N Engl J Med. 2021 Mar 4;384(9):829-841
pubmed: 33657295
Exp Anim. 2015;64(1):39-47
pubmed: 25223384
N Engl J Med. 2015 Nov 5;373(19):1814-23
pubmed: 26406150
Trends Immunol. 2004 Jan;25(1):4-7
pubmed: 14698276
Cell. 2018 Apr 5;173(2):515-528.e17
pubmed: 29625057
J Clin Oncol. 2010 Feb 20;28(6):1061-8
pubmed: 20100962
Cell Rep. 2015 Oct 13;13(2):440-9
pubmed: 26440888
N Engl J Med. 2021 Apr 8;384(14):1289-1300
pubmed: 33616314
ESMO Open. 2021 Feb;6(1):100030
pubmed: 33460963
Lancet Oncol. 2016 Jan;17(1):e4-5
pubmed: 26758760
Int J Clin Exp Med. 2015 Sep 15;8(9):14595-603
pubmed: 26628942
Eur Urol. 2013 Jul;64(1):62-70
pubmed: 22999519
N Engl J Med. 2019 Mar 21;380(12):1116-1127
pubmed: 30779529
Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9754-9
pubmed: 11493696
Ann Oncol. 2012 Jun;23(6):1549-55
pubmed: 22056973
Kidney Cancer. 2020;4(1):15-27
pubmed: 34435168
N Engl J Med. 2018 Apr 05;378(14):1277-1290
pubmed: 29562145
Ann Oncol. 2013 Sep;24(9):2409-14
pubmed: 23788753
Mol Cancer. 2020 Sep 24;19(1):145
pubmed: 32972405
Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):709s-715s
pubmed: 17255298
N Engl J Med. 2019 Mar 21;380(12):1103-1115
pubmed: 30779531
Nat Med. 2002 Aug;8(8):793-800
pubmed: 12091876
Magn Reson Imaging. 2007 Apr;25(3):319-27
pubmed: 17371720
Lancet. 2011 Dec 3;378(9807):1931-9
pubmed: 22056247
N Engl J Med. 2007 Jan 11;356(2):125-34
pubmed: 17215530