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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 11, 2020 |
| Title |
Role of androgen receptor splice variant 7 (AR-v7) in prostate cancer resistance to 2nd generation androgen receptor signaling inhibitors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Since its discovery, there has been one central issue of significant clinical relevance related to expression of the truncated androgen receptor splice variant-7 (AR-v7), which lacks the C-terminal ligand binding domain and thus acquires ligand-independent transcriptional activity in castration-resistant prostate cancer (CRPC). That question is whether AR-v7 is simply a marker of enhanced AR transcriptional activity characteristic of resistance to 2nd generation androgen receptor signaling inhibitors (ARSi) like Abiraterone and Enzalutamide, or whether it drives lethal resistance to ARSi. To address this question, the present study utilized 4 independently derived CRPC patient-derived xenografts in which the genetic and phenotypic changes could be followed before and after the development of ARSi resistance. This allowed evaluation of the correlation between acquired resistance to ARSi and changes in the expression levels of full length AR (AR-FL) vs. AR-v7 during this process. The combined results document that elevated expression of AR-FL alone is sufficient for Abiraterone- but not Enzalutamide-resistance. This is true even if AR-FL has a gain-of-function mutation. Furthermore, Enzalutamide-resistance is consistently correlated with the acquisition of AR-v7 expression. To directly test the requirement for AR-v7 expression in ARSi-refractory CRPC, CRISPR-Cas9 knockout of AR-FL and/or AR-v7 in LNCaP-95 cells was performed to evaluate in vitro and in vivo growth responses. These results document that AR-v7 drives Enzalutamide-resistance and focuses the critical need to develop therapeutic options to prevent and/or inhibit AR-v7 driven lethal progression of CRPC.
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| Overall design |
RNA sequencing of patient-derived xenograft (PDX) models using Illumina TruSeq Library prep and sequenced on Illumina HiSeq 2500.
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| Contributor(s) |
Zhu Y, Dalrymple S, Coleman I, Zheng SL, Xu J, Hooper JE, Antonarakis E, De Marzo AM, Meeker AK, Haffner MC, Yegnasubramanian S, Nelson PS, Isaacs WB, Luo J, Brennen WN, Isaacs JT |
| Citation(s) |
32989253 |
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| Submission date |
Apr 27, 2020 |
| Last update date |
Oct 29, 2020 |
| Contact name |
Ilsa Coleman |
| E-mail(s) |
icoleman@fredhutch.org
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| Phone |
206-667-1703
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| Organization name |
Fred Hutchinson Cancer Center
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| Department |
Human Biology
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| Lab |
Peter Nelson
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| Street address |
1100 Fairview Ave N, E2-112
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (13)
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| Relations |
| BioProject |
PRJNA628685 |
| SRA |
SRP258723 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE149433_RAW.tar |
8.8 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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