MP33-17 A GLUTAMINASE ISOFORM SWITCH DRIVES THERAPEUTIC RESISTANCE AND DISEASE PROGRESSION OF PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-17 A GLUTAMINASE ISOFORM SWITCH DRIVES THERAPEUTIC RESISTANCE AND DISEASE PROGRESSION OF PROSTATE CANCER Lingfan Xu XuLingfan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION OBJECTIVE: Prostate cancer is one the most common type in men. Although hormonal therapy, which targets androgen receptor (AR) signaling, efficacious initially, tumor recurrence will eventually recur. Better understanding mechanism therapy resistance and disease progression therefore exploiting new therapeutic target a pressing unmet issue. METHODS: We employed mass spectrometry isotopomer tracing technology determine metabolic flux reprogramming different stage prostate (primary, castration-resistant neuroendocrine- transdifferentiated). Immunohistochemical staining on human tissue microarrays was used expression two isoforms glutaminase (GLS1) across panel tissues diagnosed with histology results. Genetic (e.g short hairpin RNA, crispr/cas9) pharmacological (GLS1 inhibitor, CB-839) inhibition were assess biological function GLS1 as well its splicing variants cancer. Animal models established longitudinally simulate nature history drug outcomes also evaluated vivo. RESULTS: observe that therapy-resistant (including cancer, CRPC neuroendocrine NEPC) extremely addicted glutamine instead androgen, results failure AR-directed therapies. Furthermore, GLS1, key enzyme for metabolism, has functionally (KGA GAC), are differentially expressed primary recurrent KGA dominant isoform hormone-sensitive whereas GAC, much more enzymatically potent isoform, predominates NEPC. switch evidently observed animal along after being castrated. selective CB-839, shows great inhibitory effect preferentially GAC-dominant variants. CONCLUSIONS: An from drives be resistant but dependent due hyper capability GAC utilization. Therefore, would an ideal independently AR those androgen/AR-indifferent patients. Source Funding: None © 2021 American Urological Association Education Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e613-e613 Advertisement Copyright Permissions© Inc.MetricsAuthor Information Expand Loading ...