|
| Status |
Public on Feb 27, 2018 |
| Title |
Resistance to BET inhibitor leads to new therapeutic vulnerabilities in castration resistant prostate cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration resistant prostate cancer (CRPC) cells. Bromodomain and extraterminal protein (BET) inhibitors displace BRD4 protein from chromatin, resulting in the inhibition of oncogenic transcriptional programs. Several BET inhibitors (BETi) are currently being evaluated in clinical trials for a variety of malignancies, including CRPC. Here we describe a general mechanism of acquired resistance to BETi due to modulation of cellular pathways that are amenable to targeted therapies in CRPC cells. BETi resistant CRPC cells displayed cross resistance to a variety of BETi in the absence of gatekeeper mutations or persistent drug pump activation. Resistant cells exhibited reduced chromatin bound BRD4, and were less sensitive to Proteolysis Targeting Chimeric (PROTAC) -mediated degradation or genetic knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR-signaling due to CDK9-mediated serine-81 phosphorylation of AR, with a consequent increase in sensitivity to CDK9 inhibitors and enzalutamide in BETi resistant cells. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DNA damage response (DDR) genes was observed due to the loss of BRD4 from their proximal promoter regions in the resistant cells, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy in CRPC. However, data showing the reactivation of AR-signaling and increased DNA damage in the BETi resistant cells provide unique opportunities for combination therapies in managing CRPC.
|
| |
|
| Overall design |
Gene epxression by RNAseq in the parental vs BETi resistant 22RV1 and LNCaP cells
|
| |
|
| Contributor(s) |
Asangani IA |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Aug 24, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Irfan A Asangani |
| E-mail(s) |
asangani@mail.med.upenn.edu
|
| Organization name |
University of Pennsylvania
|
| Department |
Cancer Biology
|
| Lab |
Asangani
|
| Street address |
421 Curie Blvd
|
| City |
Philadelphia |
| State/province |
Pennylvania |
| ZIP/Postal code |
19104 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (6)
|
|
| Relations |
| BioProject |
PRJNA400161 |
| SRA |
SRP116233 |
Less...
More...