Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor
Bibliographic record
Abstract
// Daniel J. Coleman 1 , Kathryn Van Hook 1 , Carly J. King 1, 2 , Jacob Schwartzman 1 , Robert Lisac 1 , Joshua Urrutia 1 , Archana Sehrawat 1 , Josha Woodward 1 , Nicholas J. Wang 1, 2 , Roman Gulati 3 , George V. Thomas 1 , Tomasz M. Beer 1 , Martin Gleave 4 , James E. Korkola 1, 2 , Lina Gao 1 , Laura M. Heiser 1, 2 , Joshi J. Alumkal 1 1 OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A 2 Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, U.S.A 3 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A 4 The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada Correspondence to: Joshi J. Alumkal, email: alumkalj@ohsu.edu Keywords: genitourinary cancers: prostate, hormone signaling and inhibitors, regulation of gene expression in drug resistance, androgen receptor mutations, BET bromodomain inhibition Received: January 13, 2016 Accepted: May 07, 2016 Published: June 3, 2016 ABSTRACT Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo , demonstrating a new strategy to treat tumors harboring this mutation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 teacher head, 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".