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• W3022242763 abstract "You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III (PD64)1 Apr 2020PD64-01 THE STATUS OF THE TUMOR SUPPRESSORS VHL AND CDKN2A IMPACTS CLEAR CELL RENAL CELL CARCINOMA SENSITIVITY TO CDK 4/6 INHIBITORS Priyanka Kancherla*, Jessica Schardein, Mark R. Woodford, Sarah J. Backe, Garrett Smith, Rebecca Sager, Dimitra Bourboulia, Oleg Shapiro, Jeffery Ross, Gennady Bratslavsky, and Mehdi Mollapour Priyanka Kancherla*Priyanka Kancherla* More articles by this author , Jessica SchardeinJessica Schardein More articles by this author , Mark R. WoodfordMark R. Woodford More articles by this author , Sarah J. BackeSarah J. Backe More articles by this author , Garrett SmithGarrett Smith More articles by this author , Rebecca SagerRebecca Sager More articles by this author , Dimitra BourbouliaDimitra Bourboulia More articles by this author , Oleg ShapiroOleg Shapiro More articles by this author , Jeffery RossJeffery Ross More articles by this author , Gennady BratslavskyGennady Bratslavsky More articles by this author , and Mehdi MollapourMehdi Mollapour More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000981.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The tumor suppressor cyclin dependent kinase inhibitor 2A (CDKN2A) inhibits cyclin dependent kinase 4 (CDK4). CDKN2A is frequently mutated in renal cell carcinoma leading to hyperactive CDK4/6. Additionally CDK4/6 inhibitors have shown anti-proliferative effect in clear cell renal cell carcinoma (ccRCC) cell lines. However, the impact of the status of CDKN2A and the commonly mutated von Hippel-Lindau (VHL) tumor suppressor on the efficacy of these inhibitors in ccRCC remains elusive. The hypothesis of this study was that VHL and CDKN2A mutations affect sensitivity of ccRCC to CDK4/6 inhibitors. The objective is to determine whether VHL and CDKN2A status could serve as predictive markers for response of ccRCC to CDK4/6 inhibitors. METHODS: 1630 tumors from cases of clinically advanced ccRCC underwent comprehensive genomic profiling (CGP) using a next-generation sequencing assay. The alteration rate of CDKN2A was determined and compared between patients with mutated and wild-type VHL. VHL-null (786O, RCC4) and VHL-restored ccRCC cell lines were treated with CDK4/6 inhibitors ribociclib, palbociclib and abemaciclib. A non-tumorigenic kidney cell line (HEK293) was used as a control. Cell proliferation was examined by MTT assay and apoptosis was assessed by immunoblotting. The effect of CDKN2A re-expression by transient transfection on sensitivity of ccRCC to CDK4/6 inhibitors was analyzed by MTT assay. RESULTS: The frequency of CDKN2A genomic alteration was found to be 25.0% as determined by CGP. This suggests hyperactivity of CDK4/6, providing a rationale for targeting these kinases in ccRCC. CDKN2A was more likely to be mutated in patients with wild-type VHL compared to mutated VHL (odds ratio: 1.49, 95% confidence interval: 1.19-1.87). Of the three CDK4/6 inhibitors tested here, palbociclib was found to induce apoptosis and preferentially decrease proliferation of ccRCC cells compared to non-tumorigenic kidney cells. Palbociclib also preferentially reduced proliferation in ccRCC cells expressing the wild-type VHL gene. Lastly, restoration of CDKN2A decreased proliferation and reversed sensitivity of ccRCC cells to palbociclib. CONCLUSIONS: The FDA-approved CDK4/6 inhibitor palbociclib showed an effective response in ccRCC with wild-type VHL and mutated CDKN2A. This is consistent with hyperactivity of CDK4/6 kinases which play a prosurvival role in ccRCC. In clinical context, this data potentially identifies a cohort of patients with wild-type VHL and CDKN2A mutation who will preferentially respond to CDK4/6 inhibitors. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1298-e1298 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Priyanka Kancherla* More articles by this author Jessica Schardein More articles by this author Mark R. Woodford More articles by this author Sarah J. Backe More articles by this author Garrett Smith More articles by this author Rebecca Sager More articles by this author Dimitra Bourboulia More articles by this author Oleg Shapiro More articles by this author Jeffery Ross More articles by this author Gennady Bratslavsky More articles by this author Mehdi Mollapour More articles by this author Expand All Advertisement PDF downloadLoading ..." @default.
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• W3022242763 title "PD64-01 THE STATUS OF THE TUMOR SUPPRESSORS VHL AND CDKN2A IMPACTS CLEAR CELL RENAL CELL CARCINOMA SENSITIVITY TO CDK 4/6 INHIBITORS" @default.
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