Dataset Information

Identification of a Radiosensitivity Molecular Signature Induced by Enzalutamide in Hormone-sensitive and Hormone-resistant Prostate Cancer Cells.

ABSTRACT: Prostate cancer (PCa) is the most common cancer amongst men. A novel androgen receptor (AR) antagonist, enzalutamide (ENZA) has recently been demonstrated to enhance the effect of radiation (XRT) by impairing the DNA damage repair process. This study aimed to identify a radiosensitive gene signature induced by ENZA in the PCa cells and to elucidate the biological pathways which influence this radiosensitivity. We treated LNCaP (AR-positive, hormone-sensitive PCa cells) and C4-2 (AR-positive, hormone-resistant PCa cells) cells with ENZA alone and in combination with androgen deprivation therapy (ADT) and XRT. Using one-way ANOVA on the gene expression profiling, we observed significantly differentially expressed (DE) genes in inflammation-and metabolism-related genes in hormone-sensitive and hormone-resistant PCa cell lines respectively. Survival analysis in both the TCGA PRAD and GSE25136 datasets suggested an association between the expression of these genes and time to recurrence. These results indicated that ENZA alone or in combination with ADT enhanced the effect of XRT through immune and inflammation-related pathways in LNCaP cells and metabolic-related pathways in C4-2 cells. Kaplan-Meier analysis and Cox proportional hazard models showed that low expression of all the candidate genes except for PTPRN2 were associated with tumor progression and recurrence in a PCa cohort.

SUBMITTER: Ghashghaei M

PROVIDER: S-EPMC6586860 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Identification of a Radiosensitivity Molecular Signature Induced by Enzalutamide in Hormone-sensitive and Hormone-resistant Prostate Cancer Cells.

Ghashghaei Maryam M Niazi Tamim M TM Aguilar-Mahecha Adriana A Klein Kathleen Oros KO Greenwood Celia M T CMT Basik Mark M Muanza Thierry M TM

Scientific reports 20190620 1

Prostate cancer (PCa) is the most common cancer amongst men. A novel androgen receptor (AR) antagonist, enzalutamide (ENZA) has recently been demonstrated to enhance the effect of radiation (XRT) by impairing the DNA damage repair process. This study aimed to identify a radiosensitive gene signature induced by ENZA in the PCa cells and to elucidate the biological pathways which influence this radiosensitivity. We treated LNCaP (AR-positive, hormone-sensitive PCa cells) and C4-2 (AR-positive, hor ...[more]

PMID: 31221986

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Project description:Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ? 50% and ? 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.ClinicalTrials.gov identifier NCT01091103.

Project description:The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.

Dataset Information

Identification of a Radiosensitivity Molecular Signature Induced by Enzalutamide in Hormone-sensitive and Hormone-resistant Prostate Cancer Cells.

Publications

Identification of a Radiosensitivity Molecular Signature Induced by Enzalutamide in Hormone-sensitive and Hormone-resistant Prostate Cancer Cells.

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