Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Chatterjee, Payel; Schweizer, Michael T.; Lucas, Jared M.; Coleman, Ilsa; Nyquist, Michael D.; Frank, Sander B.; Tharakan, Robin; Mostaghel, Elahe A.; Luo, Jun; Pritchard, Colin C.; Lam, Hung; Corey, Eva; Antonarakis, Emmanuel S.; Denmeade, Samuel R.; Nelson, Peter S.

doi:10.1172/jci127613

Cited by 71 publications

(78 citation statements)

References 62 publications

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“…Potentially, tumors with DNA repair alterations are more sensitive to HDT. In a recent study, supraphysiologic androgen was shown to repress genes in DNA repair and delay restoration of damaged DNA and an enhanced effect in patients with DNA damage repair genes was observed [22]. Additionally, a case report on a germline BRCA2 and ATM positive patient treated with BAT achieved an undetectable PSA after 2 cycles, complete radiographic response after 6 cycles, and unmeasurable disease after 20 cycles [23].…”

Section: Discussionmentioning

confidence: 98%

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer

et al. 2020

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Introduction: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA).Methods: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2-4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety.Results: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6-5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed. Conclusions: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

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Section: Discussionmentioning

confidence: 98%

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer

et al. 2020

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“…This is in contrast with previous reports on prostate cancer cells, in which AR inhibition, while synthetically lethal with other treatments ( Karanika et al, 2017 ; Li et al, 2017 ), does not appear to be sufficient to induce DNA damage and downstream events by itself. In fact, a number of reports indicate that DNA damage can be induced in prostate cancer cells by overstimulation of AR activity ( Chatterjee et al, 2019 ; Lin et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Sustained androgen receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis

Ghosh

Tavernari

et al. 2020

Journal of Experimental Medicine

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Melanoma susceptibility differs significantly in male versus female populations. Low levels of androgen receptor (AR) in melanocytes of the two sexes are accompanied by heterogeneous expression at various stages of the disease. Irrespective of expression levels, genetic and pharmacological suppression of AR activity in melanoma cells blunts proliferation and induces senescence, while increased AR expression or activation exert opposite effects. AR down-modulation elicits a shared gene expression signature associated with better patient survival, related to interferon and cytokine signaling and DNA damage/repair. AR loss leads to dsDNA breakage, cytoplasmic leakage, and STING activation, with AR anchoring the DNA repair proteins Ku70/Ku80 to RNA Pol II and preventing RNA Pol II–associated DNA damage. AR down-modulation or pharmacological inhibition suppresses melanomagenesis, with increased intratumoral infiltration of macrophages and, in an immune-competent mouse model, cytotoxic T cells. AR provides an attractive target for improved management of melanoma independent of patient sex.

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“…In human prostate cancer, supraphysiological androgen levels induce senescence [70]. Recent findings by Chatterjee et al [71] confirmed that elevated androgen levels play a protective role. The present study is in agreement with the findings of Wang et al [72], demonstrating potential implications of senescence along with aging in declining male fertility.…”

Section: Discussionmentioning

confidence: 94%

Implication of Membrane Androgen Receptor (ZIP9) in Cell Senescence in Regressed Testes of the Bank Vole

Profaska-Szymik

Gałuszka

Korzekwa

et al. 2020

IJMS

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Here, we studied the impact of exposure to short daylight conditions on the expression of senescence marker (p16), membrane androgen receptor (ZIP9) and extracellular signal-regulated kinase (ERK 1/2), as well as cyclic AMP (cAMP) and testosterone levels in the testes of mature bank voles. Animals were assigned to groups based on an analysis of testis diameter, weight, seminiferous tubule diameter and the interstitial tissue area: group 1, not fully regressed (the highest parameters); group 2 (medium parameters); or group 3, regressed (the lowest parameters). Cells positive for p16 were observed only in the seminiferous tubule epithelium. However, in groups 1 and 2, these were mostly cells sloughed into the tubule lumen. In group 3, senescent cells resided in between cells of the seminiferous epithelium. Staining for ZIP9 was found in Sertoli cells. Western blot analysis showed a trend towards a decreased expression of p16 and ZIP9 in the testes of the voles in groups 2 and 3, compared to group 1. In addition, a trend towards an increased expression of ERK, as well as an increase of cAMP and testosterone levels, was revealed in group 2. In the regressed testes, a functional link exists between senescence and androgen levels with implication of ZIP9 and cAMP/ERK signaling pathways.

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Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Cited by 71 publications

References 62 publications

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer

Sustained androgen receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis

Implication of Membrane Androgen Receptor (ZIP9) in Cell Senescence in Regressed Testes of the Bank Vole

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