Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

Brennen, W. Nathaniel; Zhu, Yezi; Coleman, Ilsa M.; Dalrymple, Susan L.; Antony, Lizamma; Patel, Radhika A.; Hanratty, Brian; Chikarmane, Roshan; Meeker, Alan K.; Zheng, S. Lilly; Hooper, Jody E.; Luo, Jun; Marzo, Angelo M. De; Corey, Eva; Xu, Jianfeng; Yegnasubramanian, Srinivasan; Haffner, Michael C.; Nelson, Peter S.; Nelson, William G.; Isaacs, William B.; Isaacs, John T.

doi:10.1172/jci.insight.146827

Cited by 33 publications

(36 citation statements)

References 65 publications

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“…There are at least five different CRPC tumours reported in patients that can be classified based on AR signature and NE biomarkers: 1) AR-high tumours (ARPC) containing cancer cells expressing uniform AR and AR target genes and no NE markers; 2) AR-low tumours (ARLPC) contains cells with weak or heterogenous AR and PSA expression with no NE markers; 3) amphicrine PCa (AMPC) containing cells co-expressing AR, PSA, and NE markers; 4) small cell neuroendocrine PCa (SCNPC) containing cells with classic small cell carcinoma histology and NE marker positive and no AR and PSA expression; and 5) DNPC containing cells with neither NE marker and AR expression (8,9). These observations are recapitulated in patient-derived xenografts (8,9,(31)(32)(33)(34). Since treatment naïve PCa is predominantly AR and PSA positive tumours, the presentation of ARLPC, SCNPC, and DNPC at the late stage of tumour progression suggests that AR bypass mechanisms are adopted by these tumours.…”

Section: Heterogeneity Of Castrate-resistant Prostate Cancermentioning

confidence: 86%

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression

2022

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While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.

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Section: Heterogeneity Of Castrate-resistant Prostate Cancermentioning

confidence: 86%

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression

2022

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“…PCSK1, encoding prohormone convertase 1, belongs to the proprotein convertase family, and its overexpression has been revealed in various subtypes of neuroendocrine tumors [31][32][33]. Previous studies have shown that treatment-related NEPC also exhibits a high expression of PCSK1, and the pattern of promoter methylation was observed to be different among distinct phenotypes of PCa [34,35]. On the other hand, the role of ASXL3 and TRIM9 in the diagnosis of NEPC has not been previously shown.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Diagnosis Biomarkers for Therapy-Related Neuroendocrine Prostate Cancer

Zhang

Qian

et al. 2021

Pathol. Oncol. Res.

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Background: Therapy-related neuroendocrine prostate cancer (NEPC) is a lethal castration-resistant prostate cancer (CRPC) subtype that, at present, lacks well-characterized molecular biomarkers. The clinical diagnosis of this disease is dependent on biopsy and histological assessment: methods that are experience-based and easily misdiagnosed due to tumor heterogeneity. The development of robust diagnostic tools for NEPC may assist clinicians in making medical decisions on the choice of continuing anti-androgen receptor therapy or switching to platinum-based chemotherapy.Methods: Gene expression profiles and clinical characteristics data of 208 samples of metastatic CRPC, including castration-resistant prostate adenocarcinoma (CRPC-adeno) and castration-resistant neuroendocrine prostate adenocarcinoma (CRPC-NE), were obtained from the prad_su2c_2019 dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was subsequently used to construct a free-scale gene co-expression network to study the interrelationship between the potential modules and clinical features of metastatic prostate adenocarcinoma and to identify hub genes in the modules. Furthermore, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a model to predict the clinical characteristics of CRPC-NE. The findings were then verified in the nepc_wcm_2016 dataset.Results: A total of 51 co-expression modules were successfully constructed using WGCNA, of which three co-expression modules were found to be significantly associated with the neuroendocrine features and the NEPC score. In total, four novel genes, including NPTX1, PCSK1, ASXL3, and TRIM9, were all significantly upregulated in NEPC compared with the adenocarcinoma samples, and these genes were all associated with the neuroactive ligand receptor interaction pathway. Next, the expression levels of these four genes were used to construct an NEPC diagnosis model, which was successfully able to distinguish CRPC-NE from CRPC-adeno samples in both the training and the validation cohorts. Moreover, the values of the area under the receiver operating characteristic (AUC) were 0.995 and 0.833 for the training and validation cohorts, respectively.Conclusion: The present study identified four specific novel biomarkers for therapy-related NEPC, and these biomarkers may serve as an effective tool for the diagnosis of NEPC, thereby meriting further study.

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“…In an analysis of AR+, amphicrine, double negative, and NEPC PDXs, Brennen, et al. determined that loss of AR expression was correlated with AR promoter hypermethylation specifically in NEPC models ( 81 ). Beltran, et al.…”

Section: The Role Of Epigenetic Change In Nepc Lineage Plasticitymentioning

confidence: 99%

The Role of Epigenetic Change in Therapy-Induced Neuroendocrine Prostate Cancer Lineage Plasticity

et al. 2022

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The androgen receptor (AR) signaling pathway is critical for growth and differentiation of prostate cancer cells. For that reason, androgen deprivation therapy with medical or surgical castration is the principal treatment for metastatic prostate cancer. More recently, new potent AR signaling inhibitors (ARSIs) have been developed. These drugs improve survival for men with metastatic castration-resistant prostate cancer (CRPC), the lethal form of the disease. However, ARSI resistance is nearly universal. One recently appreciated resistance mechanism is lineage plasticity or switch from an AR-driven, luminal differentiation program to an alternate differentiation program. Importantly, lineage plasticity appears to be increasing in incidence in the era of new ARSIs, strongly implicating AR suppression in this process. Lineage plasticity and shift from AR-driven tumors occur on a continuum, ranging from AR-expressing tumors with low AR activity to AR-null tumors that have activation of alternate differentiation programs versus the canonical luminal program found in AR-driven tumors. In many cases, AR loss coincides with the activation of a neuronal program, most commonly exemplified as therapy-induced neuroendocrine prostate cancer (t-NEPC). While genetic events clearly contribute to prostate cancer lineage plasticity, it is also clear that epigenetic events—including chromatin modifications and DNA methylation—play a major role. Many epigenetic factors are now targetable with drugs, establishing the importance of clarifying critical epigenetic factors that promote lineage plasticity. Furthermore, epigenetic marks are readily measurable, demonstrating the importance of clarifying which measurements will help to identify tumors that have undergone or are at risk of undergoing lineage plasticity. In this review, we discuss the role of AR pathway loss and activation of a neuronal differentiation program as key contributors to t-NEPC lineage plasticity. We also discuss new epigenetic therapeutic strategies to reverse lineage plasticity, including those that have recently entered clinical trials.

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Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

Cited by 33 publications

References 65 publications

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression

Identification of Novel Diagnosis Biomarkers for Therapy-Related Neuroendocrine Prostate Cancer

The Role of Epigenetic Change in Therapy-Induced Neuroendocrine Prostate Cancer Lineage Plasticity

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