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
4294 - The Patient Voice: An Irish Survey of Nutrition Attitudes & Access to Dietetic Care Throughout the Cancer Journey
Presenter: Erin Stella Sullivan
Session: Poster Display session 1
Resources:
Abstract
1925 - Homcology: home chemotherapy delivery in a simultaneous care project for frail advanced cancer patients
Presenter: Claudio Chini
Session: Poster Display session 1
Resources:
Abstract
4701 - Treatment-related adverse events and tolerability in patients with advanced non-squamous non-small cell lung cancer treated with first-line checkpoint inhibitors in combination with chemotherapy
Presenter: Ruth D'cunha
Session: Poster Display session 1
Resources:
Abstract
2985 - Clinical utility of a systematic toxicity assessment form (STAF) in patients with breast cancer receiving adjuvant or neoadjuvant therapy.
Presenter: Jwa Hoon Kim
Session: Poster Display session 1
Resources:
Abstract
2358 - Physicians’ satisfaction with Health-related quality of life (HRQoL) assessment in daily clinical practice using electronic patient-reported outcome (ePRO) for cancer patients.
Presenter: Guillaume Mouillet
Session: Poster Display session 1
Resources:
Abstract
5172 - Predictors of Survival in Patients with Incurable Cancer
Presenter: Erin Stella Sullivan
Session: Poster Display session 1
Resources:
Abstract
2281 - Patients and Physicians' Satisfaction with Telemedicine (TM) in Cancer Care and Factors that Correlate with a Positive Patient’s Experience
Presenter: Hurria Gondal
Session: Poster Display session 1
Resources:
Abstract
2193 - Adherence to ESMO 2014 guidelines on bone-targeting agent (BTA) initiation for breast and prostate cancer patients: real-world insights from practicing European physicians
Presenter: Alex Rider
Session: Poster Display session 1
Resources:
Abstract
2200 - Use of skeletal-related events preventive agents in patients with solid tumours and bone metastases in central Denmark
Presenter: Anders Boysen
Session: Poster Display session 1
Resources:
Abstract
2504 - Inadequacy of current definition and staging system of Medication-Related Osteonecrosis of Jaw (MRONJ) released by AAOMS : a Computed Tomography study in 151 cancer and myeloma patients
Presenter: Vittorio Fusco
Session: Poster Display session 1
Resources:
Abstract