Revisiting the Role of p53 in Prostate Cancer

Teroerde, Miriam; Nientiedt, Cathleen; Duensing, Anette; Hohenfellner, Markus; Duensing, Stefan

doi:10.36255/exonpublications.prostatecancer.p53.2021

Cited by 16 publications

(20 citation statements)

References 82 publications

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“…Overall, our analyses are consistent with previous findings of moderate-to-low frequency of TP53 mutations in primary PC [ 13 ]. Relative to normal prostate, we found MDM4 expression to be elevated in PC, with the highest trend observed in mutant p53 PC samples.…”

Section: Resultssupporting

confidence: 92%

“…The tumour-suppressive capacity of p53 is frequently lost in PC by direct mutation [ 8 , 10 , 34 ]. TP53 mutation frequency increases (>70%) with progression to lethal metastatic PC (reviewed [ 13 ]). In PCs that retain wt p53, we hypothesized that its activities are compromised by deregulation of its key negative regulators, MDM2 and MDM4.…”

Section: Resultsmentioning

confidence: 99%

“…These results suggested that depletion of MDM4 reduced the growth of PC cell lines expressing wt p53, no p53 and even heterozygote wt/mutant p53. The latter is of interest, as most advanced metastatic PC expresses mutant p53 [ 13 ]. For a detailed characterisation of the impact of MDM4 depletion on mutant p53-expressing PC, we measured the growth kinetics and cellular responses of DU145 (p53 P223L/V274F ) using the Incucyte ® system.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, clustering of mutant p53-positive cells in the primary tumour is a powerful, clinically relevant prognostic biomarker for lethal metastatic prostate cancer [ 12 ]. As high as 73% of patients with metastatic PC have mutant p53 (as reviewed [ 13 ]).…”

Section: Introductionmentioning

confidence: 99%

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Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Mejía-Hernández

Raghu

Caramia

et al. 2022

Cancers

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Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Mejía-Hernández

Raghu

Caramia

et al. 2022

Cancers

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“…Xu et al reported a significantly shorter DFS in patients with TP53 mutated compared to wild-type TP53 ( n = 34, p = 0.003) [ 44 ]. Mutations in TP53 are among the most frequent somatic aberrations in human cancers and are frequently reported as a negative prognostic factor for survival in many solid tumour types, including lung [ 45 ], colorectal [ 46 ], breast [ 47 ], and prostate carcinoma [ 48 ], irrespective of systemic therapy. The impact of somatic pathogenic variants on the treatment outcomes of TETs should be further evaluated in patient cohorts large enough for multivariate analysis considering histopathology, stage, and treatment regimen.…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Szpechcinski¹,

Szołkowska²,

Winiarski³

et al. 2022

Cancers

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A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

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P53: A key player in diverse cellular processes including nuclear stress and ribosome biogenesis, highlighting potential therapeutic compounds

Temaj,

Chichiarelli,

Telkoparan-Akillilar

et al. 2024

Biochemical Pharmacology

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Revisiting the Role of p53 in Prostate Cancer

Cited by 16 publications

References 82 publications

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

P53: A key player in diverse cellular processes including nuclear stress and ribosome biogenesis, highlighting potential therapeutic compounds

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