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

Our plain-English summary of Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists, by L. Urso, I. Cavallari, M. Silic-Benussi, et al (Oncotarget, 2017).

The study

• Authors: L. Urso, I. Cavallari, M. Silic-Benussi, L. Biasini, G. Zago, F. Calabrese, P.F. Conte, V. Ciminale, G. Pasello
• Journal: Oncotarget
• Published: 2017;8(27):44232-44241
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study tested drugs on malignant pleural mesothelioma (MPM) cells and mice. It did not study asbestos exposure or patients. The authors used four MPM cell lines: two epithelioid (ZL55, M14K), one biphasic (MSTO211H) and one sarcomatoid (ZL34). ZL55 carried a loss-of-function p53 mutation, M14K a mutation in one copy of the gene, while the other two were not mutated. The MDM2 inhibitor Nutlin 3a activated p53 and halted the cell cycle in M14K, MSTO211H and ZL34 cells but not in ZL55. On its own it caused only a modest increase in cell death. Combined with rhTRAIL, it gave a synergistic increase in cell death in those three lines, and a caspase inhibitor blocked this. In mice injected with ZL34 cells, the related drug RG7112 plus rhTRAIL significantly reduced tumor growth compared with mock-treated mice at days 15 and 22 (p less than 0.05). Neither drug alone showed an antitumor effect. The authors concluded that this combination might offer a new treatment option, particularly for sarcomatoid MPM with MDM2 overexpression and functional inactivation of wild-type p53.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on mesothelioma cell lines (in vitro) and a mouse xenograft model (in vivo)
• Who was studied: Four human MPM cell lines: ZL55 and M14K (epithelioid), MSTO211H (biphasic) and ZL34 (sarcomatoid). For the animal work, 49 male SCID mice were injected intraperitoneally with ZL34 cells engineered to carry the luciferase gene. Four weeks later they were randomized into 4 treatment groups.
• Exposure: No asbestos exposure was studied. The exposures were drug treatments. In cells: the MDM2 inhibitor Nutlin 3a (10 µM) and/or rhTRAIL (2.56 µM). In mice: RG7112 (100 mg/Kg/die on days 1 to 21, by gavage) and/or rhTRAIL (60 mg/Kg/die on days 1 to 3, IP), or vehicle.
• Main results:
  • p53 status: ZL55 had a missense mutation with loss of heterozygosity, M14K had a monoallelic frameshift mutation, and MSTO211H and ZL34 were not mutated.
  • MDM2 mRNA and protein levels were higher in the ZL34 (sarcomatoid, wild-type p53) cell line.
  • Nutlin 3a caused accumulation in the G1 phase of the cell cycle (cell cycle arrest) in M14K, MSTO211H and ZL34 cells, but not in ZL55 cells.
  • Nutlin 3a alone caused only a modest increase in cell death in the MPM cell lines.
  • Nutlin 3a combined with rhTRAIL was synergistic (combination index below 1) in M14K, MSTO211H and ZL34 cells.
  • In these cell lines with functional p53, the cell death from Nutlin 3a plus rhTRAIL was abolished by the pan-caspase inhibitor zVAD-fmk, which the authors took to mean the apoptotic pathway was engaged.
  • In mice, RG7112 plus rhTRAIL significantly reduced tumor growth compared with mock-treated mice at days 15 and 22 (p less than 0.05). No antitumor effect was seen with either drug given alone.
• The authors' conclusion: The authors concluded that combined targeting of MDM2 and TRAIL might provide a new therapeutic option for MPM patients, particularly sarcomatoid MPM with MDM2 overexpression and functional inactivation of wild-type p53. They suggested that p53 wild-type status and high MDM2 levels may be markers for selecting patients.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Apoptosis.

Related studies

• An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression — T.T.T. Nguyen, M. Shingyoji, et al. (2021)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma — G. Pasello, L. Urso, et al. (2014)
• HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status — W.B. Ou, J. Zhu, et al. (2015)
• Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth — R.G. van der Most, A.J. Currie, et al. (2009)
• Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype — X. Ning, T.T.T. Nguyễn, et al. (2026)

Browse more research in Oncotarget, or return to medical research.