Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer

Devlies, Wout; Handle, Florian; Devos, Gaëtan; Joniau, Steven; Claessens, Frank

doi:10.3390/cancers13040915

Cited by 14 publications

(12 citation statements)

References 115 publications

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“…LNCaP and LAPC4 are hormone-sensitive PC cell lines, whereas the LNCaP sub-cell line C4-2 represents CRPC [ 17 , 19 , 20 ]. Moreover, LAPC4 expresses a wild-type AR, whereas LNCaP and C4-2 express mutated AR [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Other AR mutations associated with low antiandrogen response are L702H, W742C/L, and T878A [ 40 , 42 ]. The hormone-sensitive cell line LNCaP and its castration-resistant sub-cell line C4-2 have harbored the T878A mutation (published initially as T868A) in the ligand-binding domain of the AR, whereas LAPC4 cells express the wildtype AR [ 8 , 20 , 43 ]. Thus, the T877A mutation in the AR may explain the diminished sensitivity of LNCaP and C4-2 cells to antiandrogen efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…In the last 3 decades, several cell line models have been introduced to PC research. These include androgen-dependent cell lines (e.g., LNCaP, LAPC4, MDA PCa 2B) and androgen-independent cell lines (e.g., C4-2, PC3, Du145) [ 8 ]. In addition, several 2D and 3D primary human and mouse models have been developed [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…These include androgen-dependent cell lines (e.g., LNCaP, LAPC4, MDA PCa 2B) and androgen-independent cell lines (e.g., C4-2, PC3, Du145) [ 8 ]. In addition, several 2D and 3D primary human and mouse models have been developed [ 8 , 9 , 10 ]. These novel 2D and 3D models are closer to PC biology in patients than the established cell lines.…”

Section: Introductionmentioning

confidence: 99%

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A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

Siciliano

Simons

Beier

et al. 2021

Life

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Antiandrogen therapy is a primary treatment for patients with metastasized prostate cancer. Whilst the biologic mechanisms of antiandrogens have been extensively studied, the operating protocols used for the characterization of these drugs were not identical, limiting their comparison. Here, the antiandrogens Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide were systematically compared using identical experimental setups. Androgen-dependent LNCaP and LAPC4 cells as well as androgen-independent C4-2 cells were treated with distinct concentrations of antiandrogens. Androgen receptor (AR)-mediated gene transactivation was determined using qPCR. Cell viability was measured by WST1 assay. Protein stability and AR localization were determined using western blot. Response to the tested antiandrogens across cellular backgrounds differed primarily in AR-mediated gene transactivation and cell viability. Antiandrogen treatment in LNCaP and LAPC4 cells resulted in AR protein level reduction, whereas in C4-2 cells marginal decreased AR protein was observed after treatment. In addition, AR downregulation was already detectable after 4 h, whereas reduced AR-mediated gene transactivation was not observed before 6 h. None of the tested antiandrogens displayed an advantage on the tested parameters within one cell line as opposed to the cellular background, which seems to be the primary influence on antiandrogen efficacy. Moreover, the results revealed a prominent role in AR protein stability. It is one of the first events triggered by antiandrogens and correlated with antiandrogen efficiency. Therefore, AR stability may surrogate antiandrogen response and may be a possible target to reverse antiandrogen resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

Siciliano

Simons

Beier

et al. 2021

Life

View full text Add to dashboard Cite

show abstract

“…A variety of preclinical models for prostate cancer, including cell lines, organoids, xenografts and genetically modified mouse models, as well as numerous patient-derived xenograft (PDX) models, are now available for evaluating the origins and therapy response of prostate cancer, but each of them can only provide limited answers [ 21 ]. Further, there is an increasing amount of data published from patients suffering from prostate cancer at an early or late stage and undergoing treatment.…”

Section: Introductionmentioning

confidence: 99%

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Nevedomskaya

Haendler

2022

IJMS

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Cancer arises following alterations at different cellular levels, including genetic and epigenetic modifications, transcription and translation dysregulation, as well as metabolic variations. High-throughput omics technologies that allow one to identify and quantify processes involved in these changes are now available and have been instrumental in generating a wealth of steadily increasing data from patient tumors, liquid biopsies, and from tumor models. Extensive investigation and integration of these data have led to new biological insights into the origin and development of multiple cancer types and helped to unravel the molecular networks underlying this complex pathology. The comprehensive and quantitative analysis of a molecule class in a biological sample is named omics and large-scale omics studies addressing different prostate cancer stages have been performed in recent years. Prostate tumors represent the second leading cancer type and a prevalent cause of cancer death in men worldwide. It is a very heterogenous disease so that evaluating inter- and intra-tumor differences will be essential for a precise insight into disease development and plasticity, but also for the development of personalized therapies. There is ample evidence for the key role of the androgen receptor, a steroid hormone-activated transcription factor, in driving early and late stages of the disease, and this led to the development and approval of drugs addressing diverse targets along this pathway. Early genomic and transcriptomic studies have allowed one to determine the genes involved in prostate cancer and regulated by androgen signaling or other tumor-relevant signaling pathways. More recently, they have been supplemented by epigenomic, cistromic, proteomic and metabolomic analyses, thus, increasing our knowledge on the intricate mechanisms involved, the various levels of regulation and their interplay. The comprehensive investigation of these omics approaches and their integration into multi-omics analyses have led to a much deeper understanding of the molecular pathways involved in prostate cancer progression, and in response and resistance to therapies. This brings the hope that novel vulnerabilities will be identified, that existing therapies will be more beneficial by targeting the patient population likely to respond best, and that bespoke treatments with increased efficacy will be available soon.

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The Isoflavanoid (+)‐PTC Regulates Cell‐Cycle Progression and Mitotic Spindle Assembly in a Prostate Cancer Cell Line

Farias

Rosa‐Ribeiro

Souza

et al. 2022

Chemistry & Biodiversity

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Prostate cancer is the second most common malignancy in men and the development of effective therapeutic strategies remains challenging when more advanced, androgen-independent or insensitive forms are involved. Accordingly, we have evaluated, using flow cytometry, confocal microscopy and image analysis, the antiproliferative effects of (+)-2,3,9-trimethoxypterocarpan [(+)-PTC, 1] on relevant human prostate cancer cells as well as its capacity to control mitosis within them. In particular, the studies reported herein reveal that (+)-PTC exerts anti-proliferative activity against the PC-3 cell lines by regulating cell-cycle progression with mitosis being arrested in the prophase or prometaphase. Furthermore, it emerges that treatment of the target cells with this compound results in the formation of monopolar spindles, disorganized centrosomes and extensively disrupted γ-tubulin distributions while centriole replication remains unaffected. Such effects suggest (+)-PTC should be considered as a possible therapy for androgen-insensitive/independent prostate cancer.

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Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer

Cited by 14 publications

References 115 publications

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

The Isoflavanoid (+)‐PTC Regulates Cell‐Cycle Progression and Mitotic Spindle Assembly in a Prostate Cancer Cell Line

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