dc.date.accessioned | 2020-05-30T18:44:16Z | |
dc.date.available | 2020-05-30T18:44:16Z | |
dc.date.created | 2020-01-05T07:57:26Z | |
dc.date.issued | 2019 | |
dc.identifier.citation | Handle, Florian Prekovic, Stefan Helsen, Christine van den Broeck, Thomas Smeets, Elien Moris, Lisa Eerlings, Roy El Kharraz, Sarah Urbanucci, Alfonso Mills, Ian Geoffrey Joniau, Steven Attard, Gerhardt Claessens, Frank . Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. Scientific Reports. 2019, 9(13786), 1-11 | |
dc.identifier.uri | http://hdl.handle.net/10852/76522 | |
dc.description.abstract | Inhibition of the androgen receptor (AR) by second-generation anti-androgens is a standard treatment for metastatic castration resistant prostate cancer (mCRPC), but it inevitably leads to the development of resistance. Since the introduction of highly efficient AR signalling inhibitors, approximately 20% of mCRPC patients develop disease with AR independent resistance mechanisms. In this study, we generated two anti-androgen and castration resistant prostate cancer cell models that do not rely on AR activity for growth despite robust AR expression (AR indifferent). They are thus resistant against all modern AR signalling inhibitors. Both cell lines display cross-resistance against the chemotherapeutic drug docetaxel due to MCL1 upregulation but remain sensitive to the PARP inhibitor olaparib and the pan-BCL inhibitor obatoclax. RNA-seq analysis of the anti-androgen resistant cell lines identified hyper-activation of the E2F cell-cycle master regulator as driver of AR indifferent growth, which was caused by deregulation of cyclin D/E, E2F1, RB1, and increased Myc activity. Importantly, mCRPC tissue samples with low AR activity displayed the same alterations and increased E2F activity. In conclusion, we describe two cellular models that faithfully mimic the acquisition of a treatment induced AR independent phenotype that is cross-resistant against chemotherapy and driven by E2F hyper-activation. | en_US |
dc.language | EN | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Drivers of AR indifferent anti-androgen resistance in prostate cancer cells | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Handle, Florian | |
dc.creator.author | Prekovic, Stefan | |
dc.creator.author | Helsen, Christine | |
dc.creator.author | van den Broeck, Thomas | |
dc.creator.author | Smeets, Elien | |
dc.creator.author | Moris, Lisa | |
dc.creator.author | Eerlings, Roy | |
dc.creator.author | El Kharraz, Sarah | |
dc.creator.author | Urbanucci, Alfonso | |
dc.creator.author | Mills, Ian Geoffrey | |
dc.creator.author | Joniau, Steven | |
dc.creator.author | Attard, Gerhardt | |
dc.creator.author | Claessens, Frank | |
cristin.unitcode | 185,57,11,0 | |
cristin.unitname | Mills/Engedal Group - Prostate Cancer | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 1766327 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Scientific Reports&rft.volume=9&rft.spage=1&rft.date=2019 | |
dc.identifier.jtitle | Scientific Reports | |
dc.identifier.volume | 9 | |
dc.identifier.issue | 1 | |
dc.identifier.doi | https://doi.org/10.1038/s41598-019-50220-1 | |
dc.identifier.urn | URN:NBN:no-79602 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 2045-2322 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/76522/1/s41598-019-50220-1.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | 13786 | |
dc.relation.project | NFR/187615 | |