p53 Reactivation by PRIMA-1Met (APR-246) sensitises V600E/KBRAF melanoma to vemurafenib

Krayem, Mohammad; Journé, Fabrice; Wiedig, Murielle; Morandini, Renato; Najem, Ahmad; Salès, François; Kempen, Léon C van; Sibille, Catherine; Awada, Ahmad; Marine, Jean–Christophe; Ghanem, Ghanem Elias

doi:10.1016/j.ejca.2015.12.002

Cited by 54 publications

(50 citation statements)

References 38 publications

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“…Indeed, it was shown that p53 reactivation by PRIMA-1 Met synergizes with BRAF inhibition by vemurafenib to induce apoptosis and suppress proliferation of BRAF mutant melanoma cells in vitro . 37 As we previously showed that Tspan8 expression is also decreased by vemurafenib, 14 it can now be hypothesized that reactivating p53 and inhibiting BRAF signaling would help to decrease melanoma cells' invasiveness by repressing Tspan8 expression, and could be promising in future melanoma therapies.…”

Section: Resultsmentioning

confidence: 96%

p53 targets TSPAN8 to prevent invasion in melanoma cells

et al. 2017

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Cutaneous melanoma is a very deadly cancer because of its proclivity to metastasize. Despite the recent development of targeted and immune therapies, patient survival remains low. It is therefore crucial to enhance understanding of the molecular mechanisms underlying invasion. We previously identified tetraspanin 8 (TSPAN8) as an important modulator of melanoma invasiveness, and several of its transcriptional regulators, which affect TSPAN8 expression during melanoma progression toward an invasive stage. This study found that TSPAN8 promoter contains consensus-binding sites for p53 transcription factor. We demonstrated that p53 silencing was sufficient to turn on Tspan8 expression in non-invasive melanoma cells and that p53 acts as a direct transcriptional repressor of TSPAN8. We also showed that p53 modulated matrigel invasion in melanoma cells in a TSPAN8-dependent manner. In conclusion, this study reveals p53 as a negative regulator of Tspan8 expression. As TP53 gene is rarely mutated in melanoma, it was hitherto poorly studied but its role in apoptosis and growth suppression in melanoma is increasingly becoming clear. The study highlights the importance of p53 as a regulator of melanoma invasion and the concept that reactivating p53 could provide a strategy for modulating not only proliferative but also invasive capacity in melanoma treatment.

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Section: Resultsmentioning

confidence: 96%

p53 targets TSPAN8 to prevent invasion in melanoma cells

et al. 2017

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“…Therefore, reactivation of TP53 might be a particularly effective strategy for cancer therapy. For example, PRIMA‐1 is a direct TP53 reactivator and one of the most promising drugs …”

Section: Tp53 In Eac and Its Precursorsmentioning

confidence: 98%

Overview of major molecular alterations during progression from Barrett's esophagus to esophageal adenocarcinoma

Kalatskaya

2016

Annals of the New York Academy of Sciences

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Esophageal adenocarcinoma (EAC) develops in the sequential transformation of normal epithelium into metaplastic epithelium, called Barrett's esophagus (BE), then to dysplasia, and finally cancer. BE is a common condition in which normal stratified squamous epithelium of the esophagus is replaced with an intestine-like columnar epithelium, and it is the most prominent risk factor for EAC. This review aims to impartially systemize the knowledge from a large number of publications that describe the molecular and biochemical alterations occurring over this progression sequence. In order to provide an unbiased extraction of the knowledge from the literature, a text-mining methodology was used to select genes that are involved in the BE progression, with the top candidate genes found to be TP53, CDKN2A, CTNNB1, CDH1, GPX3, and NOX5. In addition, sample frequencies across analyzed patient cohorts at each stage of disease progression are summarized. All six genes are altered in the majority of EAC patients, and accumulation of alterations correlates well with the sequential progression of BE to cancer, indicating that the textmining method is a valid approach for gene prioritization. This review discusses how, besides being cancer drivers, these genes are functionally interconnected and might collectively be considered a central hub of BE progression.

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“…Therefore, p53 pathway defects may account more as antiapoptotic than antisenescence changes (Bennett et al, 2015). Interestingly, sensitization of BRAF mut melanomas to BRAF inhibitors can occur after restoration of the intracellular p53 levels (Krayem et al, 2016).…”

Section: Chromosomal Instabilitymentioning

confidence: 99%

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

Orfanidis

2020

Linköping University Medical Dissertations

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Melanoma is a form of cancer that develops in melanocytes. While it represents only 5% of skin malignancies, it is the most aggressive and lethal. Benign proliferation of these cells form the melanocytic nevi. The definitive diagnosis of melanocytic nevi or melanoma lesions is histopathologic. However, it is estimated that a correct diagnosis is established by means of standard skin biopsy in only 83% of the melanocytic lesions; of the remaining cases 8% and 9% are overinterpreted (false positives) and under-interpreted (false negatives), respectively. This underscores the importance of additional diagnostic tests. Since cellular senescence is considered to be a tumor suppressive mechanism, immuno-histochemistry using senescence markers has been suggested for the evaluation of difficult melanocytic lesions; however, the routinely used senescence markers lack the ability to distinguish nevi from melanoma. The general aim of this thesis is therefore to identify novel senescence markers that may aid in melanoma diagnosis.In study I, we established a cellular model with nevus-mimicking characteristics consisting in primary melanocytes that become senescent. Transcriptomic analysis allowed expanding the set of senescence-associated markers that could distinguish nevi from melanoma and identifying tubulin β-3 as a potential diagnostic marker. Depletion of tubulin β-3 and pretreatment with tubulin destabilizing drugs in melanocytes and melanoma cells induced a senescence-like phenotype in vitro. In particular, reduced migration capacity and induction of cell cycle arrest in G2/M phase of the cell cycle was demonstrated.In study II, a potential inter-cellular signaling pathway between melanoma cells and stromal fibroblasts, that might facilitate melanoma invasion, was investigated. Ultraviolet (UV) radiation was shown, both in melanoma cells and fibroblasts, to promote the release and activation of TGF-β1 and subsequent increase in expression of the serine protease FAP-α, a protein that plays role in extracellular matrix degradation and therefore facilitates the invasion of melanoma cells. Such mechanism was not functional in senescent melanocytes.In study III, it was shown that tubulin β-3 immunostaining aids in the diagnosis of nevi and melanomas. The diagnostic criterium was the tubulin β-3 gradient within the melanocytic nevi that was no longer apparent in melanoma. Different patterns of tubulin β-3 immunostaining in melanoma were described, dermoscopy-immunohistochemistry associations were found, specific dermoscopic features highlighted, and the prognostic value of this tubulin β-3 marker was examined. The progression rate in patients whose melanomas had areas with loss of tubulin β-3 was 4 times higher than in patients without this feature, although statistical significance could not be reached (p=0.06).In conclusion, transcriptomic analysis expanded the set of senescence-associated markers that could distinguish nevi from melanoma and identified tubulin β-3 as novel immunohistochemistry marker shown to have diagn...

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p53 Reactivation by PRIMA-1Met (APR-246) sensitises V600E/KBRAF melanoma to vemurafenib

Cited by 54 publications

References 38 publications

p53 targets TSPAN8 to prevent invasion in melanoma cells

p53 targets TSPAN8 to prevent invasion in melanoma cells

Overview of major molecular alterations during progression from Barrett's esophagus to esophageal adenocarcinoma

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

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