FGFR blockade by pemigatinib treats naïve and castration resistant prostate cancer

Chiodelli, Paola; Coltrini, Daniela; Turati, Marta; Cerasuolo, Marianna; Maccarinelli, Federica; Rezzola, Sara; Grillo, Elisabetta; Giacomini, Arianna; Taranto, Sara; Mussi, Silvia; Ligresti, Alessia; Presta, Marco; Ronca, Roberto

doi:10.1016/j.canlet.2021.11.030

Cited by 12 publications

(12 citation statements)

References 34 publications

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“…These findings suggested that YY1 overexpression endowed adenocarcinoma cells (LNCaP) with a mesenchymal cell phenotype, while YY1 knockout induced mesenchymal‐epithelial transition (MET) in CRPC cells. The TRAMP mouse model has been extensively used in PCa research due to the ability to accurately mimic the pathogenesis of PCa in humans 36,37 . The TRAMP model exhibits a progression from prostatic intraepithelial neoplasia (PIN; 10–12 weeks of age) to aggressive prostate adenocarcinoma (18–20 weeks of age) via the genetic expression of viral SV40 cancer protein in prostate epithelial cells 38 .…”

Section: Resultsmentioning

confidence: 99%

Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non‐canonical WNT pathway (FYN/STAT3)

Liu,

Xu,

Huang

et al. 2023

Clinical & Translational Med

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BackgroundA growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the mechanism by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity.MethodsUsing the Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, we bioinformatically analyzed YY1 expression in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells via epithelial‐mesenchymal transition induction and neuroendocrine differentiation.ResultsAndrogen deprivation therapy induced a decrease in YY1 protein ubiquitination, enhanced its stability, and thus enhanced the transcriptional activity of FZD8. Castration enhanced FZD8 binding to Wnt9A and mediated cellular plasticity by activating the non‐canonical Wnt (FZD8/FYN/STAT3) pathway.ConclusionsWe identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We believe that an in‐depth investigation of the mechanism underlying YY1‐mediated disease may lead to improved NEPC therapies.

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Section: Resultsmentioning

confidence: 99%

Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non‐canonical WNT pathway (FYN/STAT3)

Liu,

Xu,

Huang

et al. 2023

Clinical & Translational Med

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“…Given the promising results obtained in vitro and in tumor grafts in vivo, we exploited the multistage PCa tumor model represented by the TRAMP mouse, where the age-dependent transformation of the prostate starts at 8–10 weeks with intraepithelial neoplasia (PIN) and progresses to well-differentiated (WD) carcinoma [ 2 , 19 , 29 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Prostate cancer (PCa) represents the third most common malignancy worldwide and is a leading cause of death in the male population [ 1 ]. In the clinic, prostate lesions are extremely heterogeneous and characterized by different clinical behaviors ranging from premalignant to very aggressive lethal tumors [ 2 ]. To date, the standard care for PCa patients is represented by the androgen deprivation therapy (ADT) [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer

et al. 2023

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Prostate cancer (PCa) is a leading cause of death in the male population commonly treated with androgen deprivation therapy that often relapses as androgen-independent and aggressive castration-resistant prostate cancer (CRPC). Ferroptosis is a recently described form of cell death that requires abundant cytosolic labile iron to promote membrane lipid peroxidation and which can be induced by agents that inhibit the glutathione peroxidase-4 activity such as RSL3. Exploiting in vitro and in vivo human and murine PCa models and the multistage transgenic TRAMP model of PCa we show that RSL3 induces ferroptosis in PCa cells and demonstrate for the first time that iron supplementation significantly increases the effect of RSL3 triggering lipid peroxidation, enhanced intracellular stress and leading to cancer cell death. Moreover, the combination with the second generation anti-androgen drug enzalutamide potentiates the effect of the RSL3 + iron combination leading to superior inhibition of PCa and preventing the onset of CRPC in the TRAMP mouse model. These data open new perspectives in the use of pro-ferroptotic approaches alone or in combination with enzalutamide for the treatment of PCa.

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“…67 Preclinical evidence provides a rationale for targeting these alterations in PC as well; however, clinical trials are lacking. 50,68,69 Of note, five patients in our study (HNPC_3, HNPC_7, HNPC_8, HSPC_1, and HSPC_7) had genomes that were largely unaffected by SNVs/indels, CNVs, and SVs, likely due to low tumor fractions (Table S1). There may be a correlation between the tumor fraction of a sample and the number of variants called, as demonstrated by van Dessel et al 10 Thus, it is important to report the tumor fraction estimates along with sequencing data, as we did here.…”

Section: Gleasonmentioning

confidence: 94%

Exploring the tumor genomic landscape of aggressive prostate cancer by whole‐genome sequencing of tissue or liquid biopsies

Weiss,

Lamy,

Rusan

et al. 2024

Intl Journal of Cancer

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Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole‐genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone‐naïve, 15 hormone‐sensitive, and 15 castration‐resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single‐nucleotide variants or insertions/deletions included the known PC‐related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age‐related and DNA repair‐related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well‐recognized PC‐related genes are located, and also frequently affected regions near the known PC‐related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC‐related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

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FGFR blockade by pemigatinib treats naïve and castration resistant prostate cancer

Cited by 12 publications

References 34 publications

Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non‐canonical WNT pathway (FYN/STAT3)

Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non‐canonical WNT pathway (FYN/STAT3)

Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer

Exploring the tumor genomic landscape of aggressive prostate cancer by whole‐genome sequencing of tissue or liquid biopsies

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