Abstract 3441
Background
Resistance to androgen receptor signaling is arguably the principal hallmark of lethal prostate cancer. Several mechanisms account for this resistance, including mutations in the AR, restoration of signaling downstream of the pharmacological blocking and activation of alternative oncogenic pathways.
Methods
We used the Nkx3.1CreERT2/+; Ptenfloxed/floxed; p53floxed/floxed (NPp53) mice that develop CRPC upon castration and undergo neuroendocrine differentiation with anti-AR treatment to isolate Enzalutamide resistance prostate cancer cells.
Results
Recently, we showed that activation of the chromatin remodeler Nsd2 is required for PCa metastasis and is strongly associated to tumor progression, and that its silencing markedly reduced the metastatic burden and increased survival. Our current data indicates that Nsd2 silencing sensitizes PCa cells to anti-AR treatment. Nsd2 KO using CRISPR/Cas9 resulted in a markedly enhanced efficacy of Enzalutamide and a significant reduction of AR transcriptional activity with either Enzalutamide or Abiraterone using two different reporter assays. Next, To identify Nsd2-dependent AR co-regulators we immunoprecipitated chromatin-bound endogenous AR in NPp53 cells and NPp53-Nsd2KO and performed nano-LC-MS/MS mass spectrometry on the purified peptide mix. In particular, data indicates that AR association with SWI/SNF members is stronger in the absence of Nsd2, suggesting that Nsd2 overexpression might impair AR interaction to the SWI/SNF complex. We next tested whether Nsd2 in fact binds SWI/SNF subunits by co-immunoprecipitation in the NPp53 cells and whether BAF155, BAF170 and BRG1 association to AR increases in the absence of Nsd2. As suspected, there is a remarkable increase in the binding of AR to SWI/SNF subunits BAF155, BAF170 and BRG1 in the absence of Nsd2.
Conclusions
Together, our data suggests that the mechanisms by which Nsd2 overexpression drives aggressive castration resistant and androgen independent PCa may be in part through destabilizing the AR-SWI/SNF interaction and altering the specificity of the AR cistrome. Ongoing work will further elucidate this by analyzing chromatin accessibility data coupled with transcriptomics and ChIPseq data for the AR and the BAF170, BAF155 and Brg1 SWI/SNF subunits.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Alvaro Aytes.
Funding
EAU.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2791 - Efficacy of weekly paclitaxel-bevacizumab combination in advanced non squamous non-small cell lung cancer (NSCLC) : a retrospective multicentric study.
Presenter: Geoffroy Bilger
Session: Poster Display session 1
Resources:
Abstract
2916 - Post progression survival for patients treated with docetaxel/nintedanib in the SENECA trial
Presenter: Enrica Capelletto
Session: Poster Display session 1
Resources:
Abstract
1427 - Final results of randomized phase II trial of metronomic vs weekly oral vinorelbine (OV) as first-line chemotherapy (CT) in advanced NSCLC patients unfit to platinum-based CT (P-CT): Tempo-Lung EudraCT Number: 2014-003859-61
Presenter: Dariusz Kowalski
Session: Poster Display session 1
Resources:
Abstract
3789 - Pioglitazone and clarithromycin combined with metronomic low-dose chemotherapy versus nivolumab in patients with advanced non–small-cell lung cancer treated in 2nd-line and beyond: Outcomes from a randomized phase II trial (ModuLung)
Presenter: Daniel Heudobler
Session: Poster Display session 1
Resources:
Abstract
1519 - Predicting Chemotherapy Toxicity in Elderly Patients with Advanced Non-small Cell Lung Cancer: A Prospective Multicenter Study of the National Hospital Organization in Japan
Presenter: Masaki Kanazu
Session: Poster Display session 1
Resources:
Abstract
1874 - A prospective phase II trial of carboplatin (CBDCA) and nab-paclitaxel (nabPTX) for advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD)
Presenter: Toshiyuki Harada
Session: Poster Display session 1
Resources:
Abstract
3819 - Weekly Epirubicin as palliative treatment in elderly patients with malignant pleural mesothelioma.
Presenter: Paola Candido
Session: Poster Display session 1
Resources:
Abstract
3390 - Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium phase I study exploring safety and efficacy of avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates.
Presenter: Benjamin Solomon
Session: Poster Display session 1
Resources:
Abstract
5069 - Preliminary results from phase 1b study of spartalizumab plus chemotherapy for advanced non-small cell lung cancer (NSCLC)
Presenter: Armando Santoro
Session: Poster Display session 1
Resources:
Abstract
2041 - Efficacy results of selective AXL inhibitor bemcentinib with pembrolizumab following chemo in patients with NSCLC
Presenter: Jose Trigo Perez
Session: Poster Display session 1
Resources:
Abstract