Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53

Abstract

Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells. Nutlin-3A (a cis-imidazoline analogue) has been described as a potent and selective MDM2 inhibitor preventing MDM2-TP53-interaction by specific binding to the hydrophobic TP53-binding pocket of MDM2. In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2—P14/ARF. Our in vitro experiments on MPM cell lines revealed that Nutlin-3A in combination with cisplatin resulted in up to 9.75 times higher induction of senescence (p=0.0050) and up to 5 times higher apoptosis rate (p=0.0067) compared to the commonly applied cisplatin and pemetrexed regimens. Thus Nutlin-3A, a potent inhibitor of MDM2, is associated with a significant induction of senescence and apoptosis in MPM cell lines, making Nutlin-3A a promising substance for a targeted therapy in the subgroup of MPM showing MDM2 overexpression.

Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma

“…81 To restore p53 function, several small molecules, such as Nutlin-like drugs that interfere with MDM2/p53 interaction, were tested in journals.sagepub.com/home/tam 11 MPM. 82,83 In addition, NF2 has been shown to antagonize the inhibitory effect of MDM2 on p53, 84 and NF2-mutant MPM cells have been shown to be preferentially sensitive to anti-FAKtargeted therapy. 56 Consequently, co-targeting of FAK could improve MDM2-targeted therapy in MPM, probably through a coordinated mechanism that reactivates p53.…”

WDHD1 Leads to Cisplatin Resistance by Promoting MAPRE2 Ubiquitination in Lung Adenocarcinoma

“…Overexpression of the ubiquitin ligase MDM2 in malignant pleural mesothelioma is negatively correlated with patient prognosis and leads to p53 degradation and decreased cisplatin Abbreviations: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; WDHD1, WD repeat and HMG-box DNA binding protein 1; MAPRE2, microtubule-associated protein RP/EB family member 2; LUAD, lung adenocarcinoma; CO-IP, CO-immunocoprecipitation; IHC, immunohistochemical; PCR, polymerase chain reaction; siRNA, small interfering RNA. sensitivity (11). In addition, the ubiquitin ligase RNF31 is overexpressed in breast cancer tissues and MCF-7 cell lines, and it can promote polyubiquitination and degradation of p53 by stabilizing the ubiquitin ligase MDM2, which results in a reduction in cisplatin-induced apoptosis (12).…”

Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma

“…In particular, MDM2, a nuclear E3 ubiquitin ligase that binds and targets p53 for proteasomal degradation, is detected in 21.3% of clinical MPM samples, and its expression is significantly associated with poor survival [ 52 ]. To restore p53 function, several small molecules, such as the Nutlin-like drugs that disrupt MDM2/p53 interaction, have been tested in MPM [ 53 , 54 , 55 ]. Moreover, we and others have shown that the inactivation of CDKN2A/2B and TP53 is associated with an increased dependence on the G2/M checkpoint, which represents a targetable vulnerability in MPM [ 56 , 57 ].…”