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

Abstract

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.

MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data

“…The prognostic significance of MDM2 overexpression is quite controversial in the literature [ 37 ]. We found a trend towards a negative prognostic and predictive significance of high MDM2 strong nuclear expression levels, thus confirming previous results in different case series [ 19 , 29 ].…”

“…Few works have investigated the role of MDM2 expression in MPM and case series were represented mostly by epithelioid forms, thus making it difficult to draw any conclusion about different expression levels between the two main histologic subtypes [ 19 , 29 ]. Importantly, it was not clear if immunohistochemical and RT-qPCR analyses were performed on chemonaive samples, and no details about systemic and locoregional treatments of affected patients were reported, which might have some impact on survival data.…”

“…p53 reactivation through MDM2 inhibitors seems to be a promising strategy to sensitize p53 wild-type cancer cells to apoptosis, especially when MDM2 overexpression is present [ 15 , 16 ]. Wild-type p53 might be present in MPM specimen [ 17 , 18 ], even though few data about MDM2 expression levels are available [ 19 ].…”

Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy

“…In previous studies, we have demonstrated that MDM2 is overexpressed in approximately 20-30% of MPM and this finding was restricted to epitheloid MPM or the epithelioid components of biphasic MPM 78 , 79 . Moreover, patients with MDM2 -positive MPM presented with a significantly decreased OS compared to MDM2 -negative MPM 78 , 79 . The physiological inhibitor of MDM2 is P14/ARF and loss of P14/ARF activity may have a similar effect as loss of TP53 80 - 83 .…”

The Roles of MDM2 and MDMX in Cancer

“…For example, one study reported that high levels of MDM2 expression correlated with poor survival in mesothelioma patients (86). Significantly, in a 2015 study, MDM2 has been shown to be an important prognostic and predictive marker for response to platin–pemetrexed therapy (antifolates and platin derivatives) in patients with malignant pleural mesothelioma (87). …”