Abstract LB-59: ERG induces taxane resistance in castration-resistant prostate cancer.
Bibliographic record
Abstract
Abstract Taxanes are the only chemotherapies to prolong survival for patients with metastatic castration-resistant prostate cancer (CRPC), and both docetaxel (doc) and cabazitaxel (cab) are FDA approved for this indication. Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study we show that ERG over-expression, which occurs in roughly 50% of prostate cancers, is associated with both doc and cab resistance using in vitro and in vivo models of CRPC. Using either tetracycline-inducible or constitutively active expression systems in multiple prostate cancer cell lines, we found that ERG over-expression leads to at least a 10 fold increase in IC50 doses of doc or cab based on cell viability assays and inhibition of taxane-induced apoptosis. Similarly, ERG over-expressing prostate cancer xenografts were reproducibly more resistant to cab compared to the cab-sensitive control xenografts. Based on a biochemical and cell biological characterization, we observed that ERG binds directly to tubulin in the cytoplasm of prostate cancer cells, as well as in circulating tumor cells from patients treated with doc, and prevents taxane-induced microtubule stabilization. ERG over-expression affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of doc or cab with tubulin, either directly via its tubulin interaction or indirectly by affecting transcription of genes that modulate microtubule homeostasis. In addition, ERG induces and binds to clusterin, a molecular chaperone also associated with taxane resistance. Clusterin knock-down with siRNA abrogates ERG-induced taxane resistance. Altogether, this data suggests that ERG, an oncogenic transcription factor, plays a novel role beyond regulating gene expression and functions outside the nucleus to cooperate with clusterin and tubulin in promoting taxane resistance. Determining ERG status in patient tumors may aid in patient selection for doc or cab therapy and/or influence co-targeting approaches using the clusterin antisense inhibitor OGX-011. Citation Format: Giuseppe Galletti, Himisha Beltran, Alexandre Matov, Jacqueline Fontugne, Juan Miguel Mosquera, Ladan Fazli, Scott Tagawa, David Nanus, Martin Gleave, Mark Rubin, Paraskevi Giannakakou, David S. Rickman. ERG induces taxane resistance in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-59. doi:10.1158/1538-7445.AM2013-LB-59
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".