Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration‐resistant prostate cancer (CRPC)

Pal, Sumanta K.; Patel, Jaymala; He, Miaoling; Foulk, Brad; Kraft, Katherine; Smirnov, Denis A.; Twardowski, Przemyslaw; Kortylewski, Marcin; Bhargava, Vipul; Jones, Jeremy O.

doi:10.1002/cncr.31161

Cited by 58 publications

(50 citation statements)

References 28 publications

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“…6C; Supplementary Table S3). The lack of a durable response to androgen-or AR-targeted therapy is a major challenge in CRPC management (7). Transactivation of AR by growth factors and cytokines is one of many mechanisms that drive progression to castration resistance (15).…”

Section: Analysis Of Tumor Samplesmentioning

confidence: 99%

“…ENZA inhibits ligand binding to the AR, subsequent AR nuclear translocation, recruitment of AR co-activators and AR binding to DNA, and prevents transcription of essential genes that promote tumor growth (6) (https://www.medicines.org.uk/emc/product/10318/smpc). While ENZA has shown efficacy in CRPC, most patients develop resistance and some exhibit de novo resistance (7).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antitumor Activity of the IGF-1/IGF-2–Neutralizing Antibody Xentuzumab (BI 836845) in Combination with Enzalutamide in Prostate Cancer Models

Weyer-Czernilofsky

Hofmann

Friedbichler

et al. 2020

Molecular Cancer Therapeutics

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received research support from Boehringer Ingelheim. T. Bogenrieder holds ownership interest (including patents) in Roche, Seattle Genetics, Celgene, Gilead, and Immunogen. H.M. Nguyen declares no conflict of interest. Authors' Contributions U. Weyer-Czernilofsky had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Section: Analysis Of Tumor Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of the IGF-1/IGF-2–Neutralizing Antibody Xentuzumab (BI 836845) in Combination with Enzalutamide in Prostate Cancer Models

Weyer-Czernilofsky

Hofmann

Friedbichler

et al. 2020

Molecular Cancer Therapeutics

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“…To determine whether CTC‐enriched samples have the potential to yield gene expression data that is clinically and biologically relevant to PC, patient samples were analyzed for expression of PC‐relevant genes and pathways. These were identified by curating the PC literature and by querying the expression of candidate genes in whole blood using the Genotype Tissue Expression portal 13,29,39–42 . Predictably, in the engineered cancer:WBC control samples, PC‐relevant gene expression increased with higher proportions of cancer cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These were identified by curating the PC literature and by querying the expression of candidate genes in whole blood using the Genotype Tissue Expression portal. 13,29,[39][40][41][42] Predictably, in the engineered cancer:WBC control samples, PC-relevant gene expression increased with higher proportions of cancer cells (Fig. 5a).…”

Section: Rna-seq Of Cancer Cells Enriched From Bloodmentioning

confidence: 95%

Cancer transcriptomic profiling from rapidly enriched circulating tumor cells

Morrison

Cunha

Jojo

et al. 2020

Intl Journal of Cancer

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Transcriptomic profiling of metastatic cancer can illuminate mechanisms of progression and lead to new therapies, but standard biopsy is invasive and reflects only a single metastatic site. In contrast, circulating tumor cell (CTC) profiling is noninvasive and repeatable, reflecting the dynamic and systemic nature of advanced disease. To date, transcriptomic profiling of CTCs has not delivered on its full potential, because white blood cells (WBCs) vastly outnumber CTCs. Current profiling strategies either lack cancer sensitivity and specificity or require specialized CTC capture protocols that are not readily scalable to large patient cohorts. Here, we describe a new strategy for rapid CTC enrichment and transcriptomic profiling using commercially available WBC depletion, microfluidic enrichment and RNA sequencing. When applied to blood samples from patients with advanced prostate cancer (PC), transcriptomes from enriched samples cluster with cancer positive controls and previously undetectable prostate‐specific transcripts become readily measurable. Gene set enrichment analysis reveals multiple significantly enriched signaling pathways associated with PC, as well as novel pathways that merit further study. This accessible and scalable approach yields cancer‐specific transcriptomic data and can be applied repeatedly and noninvasively in large cancer patient cohorts to discover new therapeutic targets in advanced disease.

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“…Gain-of-function mutations in the AR gene, especially within the exon 7 (encoding for the ligand-binding domain), have been found in 5–30% of CRPC patients ( Taplin et al 1999 , Coutinho et al 2016 , Kumar et al 2016 , Rathkopf et al 2017 , Pal et al 2018 ). These genomic alterations do not only permit receptor activation by various circulating steroids next to testosterone (such as H875Y or T878A), but may also alter the responsiveness of the AR to antiandrogens, resulting in antagonist-to-agonist switching ( Grossmann et al 2001 , Nadal et al 2017 , Prekovic et al 2018 a ).…”

Section: Molecular Basis Underlying Enzalutamide Resistancementioning

confidence: 99%

Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond

Linder

Poel

Bergman

et al. 2019

Endocrine-Related Cancer

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The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.

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Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration‐resistant prostate cancer (CRPC)

Cited by 58 publications

References 28 publications

Antitumor Activity of the IGF-1/IGF-2–Neutralizing Antibody Xentuzumab (BI 836845) in Combination with Enzalutamide in Prostate Cancer Models

Antitumor Activity of the IGF-1/IGF-2–Neutralizing Antibody Xentuzumab (BI 836845) in Combination with Enzalutamide in Prostate Cancer Models

Cancer transcriptomic profiling from rapidly enriched circulating tumor cells

Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond

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