Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients

Bahnassy, Abeer A.; Zekri, Abdel‐Rahman N.; Abou-Bakr, Amany A; El-Deftar, Mervat M.; Bastawisy, Ahmed El; Sakr, Mohamed; El-Sherif, Ghada M.; Gaafar, Rabab

doi:10.1016/j.yexmp.2012.04.001

Cited by 20 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P16/INK2A and P14/ARF are controlled by distinct promoters and differ in one exon leading to two unique proteins that are structurally different ( Kanellou et al , 2009 ). Deletion of the whole CDKN2A locus, on chromosome 9p21, is present in 79–90% of all malignant mesotheliomas; in the sarcomatoid subtype, the prevalence is up to 100% ( Frew et al , 2009 ; Krasinskas et al , 2010 ; Altomare et al , 2011 ; Monaco et al , 2011 ; Bahnassy et al , 2012 ; Matsumoto et al , 2013 ; Tochigi et al , 2013 ). The inactivation of the CDKN2A locus occurs also without deletion.…”

Section: Discussionmentioning

confidence: 99%

MDM2 is an important prognostic and predictive factor for platin–pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53

et al. 2015

View full text Add to dashboard Cite

Background:Malignant pleural mesothelioma (MPM) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed. Until now, predictive and prognostic biomarkers are lacking, making it a non-tailored therapy regimen with unknown outcome. P53 is frequently inactivated in MPM, but mutations are extremely rare. MDM2 and P14/ARF are upstream regulators of P53 that may contribute to P53 inactivation.Methods:A total of 72 MPM patients were investigated. MDM2 immunoexpression was assessed in 65 patients. MDM2 and P14/ARF mRNA expression was analysed in 48 patients of the overall collective. The expression results were correlated to overall survival (OS) and progression-free survival (PFS).Results:OS and PFS correlated highly significantly with MDM2 mRNA and protein expression, showing a dismal prognosis for patients with elevated MDM2 expression (for OS: Score (logrank) test: P⩽0.002, and for PFS: Score (logrank) test; P<0.007). MDM2 was identified as robust prognostic and predictive biomarker for MPM on the mRNA and protein level. P14/ARF mRNA expression reached no statistical significance, but Kaplan–Meier curves distinguished patients with low P14/ARF expression and hence shorter survival from patients with higher expression and prolonged survival.Conclusions:MDM2 is a prognostic and predictive marker for a platin–pemetrexed therapy of patients with MPMs. Downregulation of P14/ARF expression seems to contribute to MDM2-overexpression-mediated P53 inactivation in MPM patients.

show abstract

Section: Discussionmentioning

confidence: 99%

MDM2 is an important prognostic and predictive factor for platin–pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53

et al. 2015

View full text Add to dashboard Cite

show abstract

“…We reasoned that MPM might be a good model to test this combination because of its frequent MDM2 overexpression [ 20 ] and low rate of p53 mutation [ 36 ]. Importantly, higher expression levels of MDM2 characterize sarcomatoid/biphasic compared to epithelioid MPM samples [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nutlin 3a and RG7112 are particularly effective in cancer cells overexpressing MDM2, while they are ineffective in cancer cells with downstream defects in the p53 pathway [ 18 ] or in cells overexpressing MDMX [ 19 ]. MDM2 overexpression has been previously reported in MPM samples, especially in the sarcomatoid and biphasic subtypes [ 20 , 21 ], where it might represent a promising therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists

et al. 2017

View full text Add to dashboard Cite

Malignant Pleural Mesothelioma (MPM) is a chemoresistant tumor characterized by low rate of p53 mutation and upregulation of Murine Double Minute 2 (MDM2), suggesting that it may be effectively targeted using MDM2 inhibitors. In the present study, we investigated the anticancer activity of the MDM2 inhibitors Nutlin 3a (in vitro) and RG7112 (in vivo), as single agents or in combination with rhTRAIL.In vitro studies were performed using MPM cell lines derived from epithelioid (ZL55, M14K), biphasic (MSTO211H) and sarcomatoid (ZL34) MPMs. In vivo studies were conducted on a sarcomatoid MPM mouse model.In all the cell lines tested (with the exception of ZL55, which carries a biallelic loss-of-function mutation of p53), Nutlin 3a enhanced p21, MDM2 and DR5 expression, and decreased survivin expression. These changes were associated to cell cycle arrest but not to a significant induction of apoptosis. A synergistic pro-apoptotic effect was obtained through the association of rhTRAIL in all the cell lines harboring functional p53. This synergistic interaction of MDM2 inhibitor and TRAIL agonist was confirmed using a mouse preclinical model. Our results suggest that the combined targeting of MDM2 and TRAIL might provide a novel therapeutic option for treatment of MPM patients, particularly in the case of sarcomatoid MPM with MDM2 overexpression and functional inactivation of wild-type p53.

show abstract

“…The elevated synthesis of ROS generated from inflammatory and epithelial cells, results in nuclear genotoxic events (Yao et al, 2010;Huang et al, 2012) and genetic aberrations that lead to altered expression of some cell cycle regulatory genes (Bahnassy et al, 2012). Genotoxic agents such as chemicals, radiation and asbestos, are able to induce p53 mediated responses in A549 involved in the decision of the cell to undergo apoptosis or to proliferate even after DNA damage (Hevel et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Raw and thermally treated cement asbestos exerts different cytotoxicity effects on A549 cells in vitro

et al. 2015

View full text Add to dashboard Cite

Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients

Cited by 20 publications

References 31 publications

MDM2 is an important prognostic and predictive factor for platin–pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53

MDM2 is an important prognostic and predictive factor for platin–pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53

Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists

Raw and thermally treated cement asbestos exerts different cytotoxicity effects on A549 cells in vitro

Contact Info

Product

Resources

About