MP73-07 INVOLVEMENT OF ANGIOGENIN IN SUNITINIB RESISTANCE IN HUMAN RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2017MP73-07 INVOLVEMENT OF ANGIOGENIN IN SUNITINIB RESISTANCE IN HUMAN RENAL CELL CARCINOMA Laure Pierard, Sébastien Bergerat, Claire Béraud, Pascal Mouracade, Imène Hamaidi, Catherine Coquard, Sylvie Rothhut, Véronique Lindner, Hervé Lang, and Thierry Massfelder Laure PierardLaure Pierard More articles by this author , Sébastien BergeratSébastien Bergerat More articles by this author , Claire BéraudClaire Béraud More articles by this author , Pascal MouracadePascal Mouracade More articles by this author , Imène HamaidiImène Hamaidi More articles by this author , Catherine CoquardCatherine Coquard More articles by this author , Sylvie RothhutSylvie Rothhut More articles by this author , Véronique LindnerVéronique Lindner More articles by this author , Hervé LangHervé Lang More articles by this author , and Thierry MassfelderThierry Massfelder More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3352AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clear cell renal cell carcinoma (CCC), the main subtype of kidney cancer, represents 250 000 cases and 110 000 deaths worldwide/year. In 75% of cases there is a loss of the von Hippel-Lindau (VHL) tumor suppressor gene that is involved in hypoxia inducible factors (HIF) degradation. Current targeted therapies for advanced CCC arise from the knowledge of the VHL/HIF system. These include sunitinib, sorafenib and everolimus. Their efficiency is however limited due to acquired resistance. Since the classical mechanisms of resistance are not involved in CCC, we hypothesized that signalling pathways and/or markers are involved in such resistance. We focused here on sunitinib. METHODS We used a panel of CCC cell lines expressing VHL (Caki-1, Caki-2, ACHN) or not (786-0, A498) and tumor/normal tissues pairs from 50 CCC patients. We analyzed tumor growth in response to sunitinib both in vitro using Cristal Violet assay and in vivo using the xenografted nude mice tumor model (40 mg/kg, 3 times/week, 4 weeks, per os). We analyzed protein expression and signaling pathways by RT-qPCR, Western blot, proteome arrays specific for phosphokinases, apoptosis and angiogenesis and with the HTG EdgeSeq oncology biomarker panel assay (2560 genes of 24 signaling pathways). RESULTS In vitro, sunitinib inhibited cell growth of all cell lines tested by up to 85%. In vivo, however, xenografted 786-0 and A498 tumors were resistant to sunitinib. By analyzing A498 tumors we identified, among others, angiogenin (Ang), a pro-angiogenic factor, as being stimulated more than 10 fold by sunitinib. The stimulation of Ang by sunitinib was also observed in all cell lines. Interestingly, in tissue pairs, the expression of Ang was found to be deregulated in 75% of tumors, regardless of tumor stage and grade. Ang stimulates rRNA transcription after nuclear translocation and activates oncogenic signaling pathways (Akt, JunK, MAPK) through a uncharacterized transmembrane receptor. Ang expression and activity has never been functionally linked to sunitinib. In 786-0 tumors-bearing nude mice, tumoral growth was inhibited by 30% by neamine, an inhibitor of Ang nuclear translocation, but it had no effect on sunitinib resistance. Akt and GSK-3 were also activated in vitro and in vivo by sunitinib. We are now performing in vivo studies using siRNA targeting Ang allowing to also inhibit its effect on oncogenic pathways, alone and in combination with sunitinib. CONCLUSIONS Taken together, these results strongly suggest that Ang is involved in sunitinib resistance in human CCC, opening new therapeutic option for this refractory disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e966 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Laure Pierard More articles by this author Sébastien Bergerat More articles by this author Claire Béraud More articles by this author Pascal Mouracade More articles by this author Imène Hamaidi More articles by this author Catherine Coquard More articles by this author Sylvie Rothhut More articles by this author Véronique Lindner More articles by this author Hervé Lang More articles by this author Thierry Massfelder More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...