The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma
Helena Polena, Julie Creuzet, Maeva Dufies, Adama Sidibé, Abir Khalil-Mgharbel, Aude Salomon, Alban Deroux, Jean-Louis Quesada, Caroline Roelants, Odile Filhol, Claude Cochet, Ellen Blanc, Céline Ferlay-Segura, Delphine Borchiellini, Jean-Marc Ferrero, Bernard Escudier, Sylvie Négrier, Gilles Pages, Isabelle Vilgrain, Helena Polena, Julie Creuzet, Maeva Dufies, Adama Sidibé, Abir Khalil-Mgharbel, Aude Salomon, Alban Deroux, Jean-Louis Quesada, Caroline Roelants, Odile Filhol, Claude Cochet, Ellen Blanc, Céline Ferlay-Segura, Delphine Borchiellini, Jean-Marc Ferrero, Bernard Escudier, Sylvie Négrier, Gilles Pages, Isabelle Vilgrain
Abstract
Background: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome.
Methods: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials).
Results: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab.
Conclusions: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.
Trial registration: ClinicalTrials.gov NCT00619268 NCT00943839.
Conflict of interest statement
The authors declare no competing interest.
Figures
References
- Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210.
- Afriansyah A, Hamid AR, Mochtar CA, Umbas R. Targeted therapy for metastatic renal cell carcinoma. Acta Med. Indones. 2016;48:335–347.
- Yang JC, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 2003;349:427–434. doi: 10.1056/NEJMoa021491.
- Escudier B, et al. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br. J. Cancer. 2014;110:2821–2828. doi: 10.1038/bjc.2014.244.
- Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 2007;356:115–124. doi: 10.1056/NEJMoa065044.
- Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 2009;27:3584–3590. doi: 10.1200/JCO.2008.20.1293.
- Motzer RJ, Escudier B, Gannon A, Figlin RA. Sunitinib: ten years of successful clinical use and study in advanced renal cell carcinoma. Oncologist. 2017;22:41–52. doi: 10.1634/theoncologist.2016-0197.
- Huang D, et al. Sunitinib acts primarily on tumour endothelium rather than tumour cells to inhibit the growth of renal cell carcinoma. Cancer Res. 2010;70:1053–1062. doi: 10.1158/0008-5472.CAN-09-3722.
- Dufies M, et al. Sunitinib stimulates expression of VEGFC by tumour cells and promotes lymphangiogenesis in clear cell renal cell carcinomas. Cancer Res. 2017;77:1212–1226. doi: 10.1158/0008-5472.CAN-16-3088.
- Giuliano S, et al. Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux. Autophagy. 2015;11:1891–1904. doi: 10.1080/15548627.2015.1085742.
- Joosten SC, et al. Resistance to sunitinib in renal cell carcinoma: from molecular mechanisms to predictive markers and future perspectives. Biochim. Biophys. Acta. 2015;1855:1–16.
- Karashima T, et al. Expression of angiogenesis-related gene profiles and development of resistance to tyrosine-kinase inhibitor in advanced renal cell carcinoma: characterization of sorafenib-resistant cells derived from a cutaneous metastasis. Int. J. Urol. 2013;20:923–930. doi: 10.1111/iju.12084.
- Dejana E, Tournier-Lasserve E, Weinstein BM. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev. Cell. 2009;16:209–221. doi: 10.1016/j.devcel.2009.01.004.
- Bouillet L, et al. Endothelial junctions: exploiting their instability in the development of biomarkers for vascular remodelling. Med. Sci. 2014;30:633–635.
- Wallez Y, et al. Src kinase phosphorylates vascular endothelial-cadherin in response to vascular endothelial growth factor: identification of tyrosine 685 as the unique target site. Oncogene. 2007;26:1067–1077. doi: 10.1038/sj.onc.1209855.
- Lambeng N, et al. Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues. Circ. Res. 2005;96:384–391. doi: 10.1161/01.RES.0000156652.99586.9f.
- Sidibé A, et al. Dynamic phosphorylation of VE-cadherin Y685 throughout mouse estrous cycle in ovary and uterus. Am. J. Physiol. Heart Circ. Physiol. 2014;307:H448–H454. doi: 10.1152/ajpheart.00773.2013.
- Sidibé A, et al. Soluble vascular-endothelial (VE)-cadherin: toward a marker of endothelial dysfunction. In: Feige JJ, Pagès G, Soncin F, et al., editors. Molecular Mechanisms of Angiogenesis. France: Springer-Verlag; 2014. pp. 461–478.
- Sidibé A, et al. Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumour necrosis factor α-induced VE-cadherin cleavage. Arthritis Rheum. 2012;64:77–87. doi: 10.1002/art.33336.
- Vilgrain I, et al. Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumours: towards a candidate biomarker. PLoS ONE. 2013;8:e80056. doi: 10.1371/journal.pone.0080056.
- Rochefort P, et al. Soluble VE-cadherin in metastatic breast cancer: an independent prognostic factor for both progression-free survival and overall survival. Br. J. Cancer. 2017;116:356–361. doi: 10.1038/bjc.2016.427.
- Lê J, et al. Quantitative zymography of matrix metalloproteinases by measuring hydroxyproline: application to gelatinases A and B. Electrophoresis. 1999;20:2824–2829. doi: 10.1002/(SICI)1522-2683(19991001)20:14<2824::AID-ELPS2824>;2-H.
- Dufies M, et al. CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas. Br. J. Cancer. 2017;117:947–953. doi: 10.1038/bjc.2017.276.
- Kluger HM, et al. Classification of renal cell carcinoma based on expression of VEGF and VEGF receptors in both tumour cells and endothelial cells. Lab. Invest. 2008;88:962–972. doi: 10.1038/labinvest.2008.65.
- Cunningham D, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–1418. doi: 10.1016/S0140-6736(98)02309-5.
- Figlin RA. Mechanisms of disease: survival benefit of temsirolimus validates a role for mTOR in the management of advanced RCC. Nat. Clin. Pract. Oncol. 2008;5:601–609. doi: 10.1038/ncponc1173.
- Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer. 2016;16:131–144. doi: 10.1038/nrc.2016.14.
- Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278:16–27. doi: 10.1111/j.1742-4658.2010.07919.x.
- Senger DR, et al. Vascular permeability factor (VPF, VEGF) in tumour biology. Cancer Metastas. Rev. 1993;12:303–324. doi: 10.1007/BF00665960.
- Di Desidero T, et al. Antiproliferative and proapoptotic activity of sunitinib on endothelial and anaplastic thyroid cancer cells via inhibition of Akt and ERK1/2 phosphorylation and by down-regulation of cyclin-D1. J. Clin. Endocrinol. Metab. 2013;98:E1465–E1473. doi: 10.1210/jc.2013-1364.
- Motzer RJ, et al. Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumour markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma. Cancer Chemother. Pharmacol. 2014;74:739–750. doi: 10.1007/s00280-014-2539-0.
- Kamiyama H, Takano S, Tsuboi K, Matsumura A. Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells. J. Cancer Res. Clin. Oncol. 2005;131:205–213. doi: 10.1007/s00432-004-0642-z.
- Tien WS, Chen JH, Wu KP. Sheddome DB: the ectodomain shedding database for membrane-bound shed markers. BMC Bioinform. 2017;18:1465–1467. doi: 10.1186/s12859-017-1465-7.
- De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer. 2017;17:457–474. doi: 10.1038/nrc.2017.51.
- Bartolomé RA, et al. VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers. Oncotarget. 2017;8:215–227. doi: 10.18632/oncotarget.13832.
- Stubbs C, et al. A study of angiogenesis markers in patients with renal cell carcinoma undergoing therapy with sunitinib. Anticancer Res. 2017;37:253–259. doi: 10.21873/anticanres.11315.
- Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities. Invest. New Drug. 2012;30:2066–2079. doi: 10.1007/s10637-012-9796-8.
- Pastore AL, et al. Serum and urine biomarkers for human renal cell carcinoma. Dis. Markers. 2015;2015:251403. doi: 10.1155/2015/251403.
- Bauman TM, Huang W, Lee MH, Abel EJ. Neovascularity as a prognostic marker in renal cell carcinoma. Hum. Pathol. 2016;57:98–105. doi: 10.1016/j.humpath.2016.07.005.
- Blanchet B, et al. Development and validation of an HPLC-UV-visible method for sunitinib quantification in human plasma. Clin. Chim. Acta. 2009;404:134–139. doi: 10.1016/j.cca.2009.03.042.
- Sabanathan D, et al. Dose individualization of sunitinib in metastatic renal cell cancer: toxicity-adjusted dose or therapeutic drug monitoring. Cancer Chemother. Pharmacol. 2017;80:385–393. doi: 10.1007/s00280-017-3362-1.
- Cabel L, et al. Drug monitoring of sunitinib in patients with advanced solid tumours: a monocentric observational French study. Fundam. Clin. Pharmacol. 2018;32:98–107. doi: 10.1111/fcp.12327.
- Fernando NT, et al. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin. Cancer Res. 2008;14:1529–1539. doi: 10.1158/1078-0432.CCR-07-4126.
- Négrier S, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673–680. doi: 10.1016/S1470-2045(11)70124-3.
- Bhojani N, et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur. Urol. 2008;53:917–930. doi: 10.1016/j.eururo.2007.11.037.
- Noé G, et al. Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib. Oncotarget. 2016;7:67507–67520. doi: 10.18632/oncotarget.11686.
Source: PubMed