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

Loredana Urso,Pier Franco Conte,Ilaria Cavallari,Giulia Zago,Lorena Biasini,Vincenzo Ciminale,Fiorella Calabrese,Giulia Pasello,Micol Silic-Benussi

doi:10.18632/oncotarget.17790

Abstract

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.

Highlights

Malignant Pleural Mesothelioma (MPM) is a rare cancer with poor prognosis and increasing incidence [1]
The molecular pathogenesis of MPM is characterized by frequent deletion of the INK4A/ARF locus (70–80%), which encodes p14/ARF and p16/INK4A, while p53 is not mutated in the majority of the cases [5, 6]. p14/ARF, an inhibitor of Murine Double Minute 2 (MDM2), is crucial in the control of cell proliferation [7]
Malignant Pleural Mesothelioma is a highly lethal disease, which is poorly responsive to current therapies [3, 4], for the sarcomatoid subtype [27]

Summary

INTRODUCTION

Malignant Pleural Mesothelioma (MPM) is a rare cancer with poor prognosis and increasing incidence [1]. P53 reactivation by MDM2 inhibitors sensitizes p53 wild-type cancer cells to DNA damaging agents, which trigger the intrinsic pathway of apoptosis, or to extrinsic apoptosis activators such as TRAIL (Tumor necrosis factor (TNF)-related apoptosis-inducing ligand) [14,15,16,17]. 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. Building on these findings, in the present study we investigated the combination of rhTRAIL and Nutlin 3a or RG7112, in p53 wild type MPM cells, in vitro and in a preclinical MPM model

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS