Perifosine as a potential novel anti-cancer agent inhibits EGFR/MET-AKT axis in malignant pleural mesothelioma

Our plain-English summary of Perifosine as a potential novel anti-cancer agent inhibits EGFR/MET-AKT axis in malignant pleural mesothelioma, by G. Pinton, A.G. Manente, G. Angeli, et al (PloS One, 2012).

The study

• Authors: G. Pinton, A.G. Manente, G. Angeli, L. Mutti, L. Moro
• Journal: PloS One
• Published: 2012;7(5):e36856
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: PI3K/AKT signalling pathway is aberrantly active and plays a critical role for cell cycle progression of human malignant pleural mesothelioma (MMe) cells. AKT is one of the important cellular targets of perifosine, a novel bio-available alkylphospholipid that has displayed significant anti-proliferative activity in vitro and in vivo in several human tumour model systems and is currently being tested in clinical trials.

Methods: We tested Perifosine activity on human mesothelial cells and different mesothelioma cell lines, in order to provide evidence of its efficacy as single agent and combined therapy.

Results: We demonstrate here that perifosine, currently being evaluated as an anti-cancer agent in phase 1 and 2 clinical trials, caused a dose-dependent reduction of AKT activation, at concentrations causing MMe cell growth arrest. In this study we firstly describe that MMe cells express aside from AKT1 also AKT3 and that either the myristoylated, constitutively active, forms of the two proteins, abrogated perifosine-mediated cell growth inhibition. Moreover, we describe here a novel mechanism of perifosine that interferes, upstream of AKT, affecting EGFR and MET phosphorylation. Finally, we demonstrate a significant increase in cell toxicity when MMe cells were treated with perifosine in combination with cisplatin.

Conclusions: This study provides a novel mechanism of action of perifosine, directly inhibiting EGFR/MET-AKT1/3 axis, providing a rationale for a novel translational approach to the treatment of MMe.

In plain English

This was a laboratory study of cells grown in dishes, not of patients, and it did not study asbestos exposure. The authors tested perifosine, an experimental cancer drug, on three malignant pleural mesothelioma cell lines (REN, MSTO-211H and MMP) and on normal mesothelial cells (HMC). After 24 hours, the dose that halved growth was printed as 23, 14 and 7.5 mM for REN, MSTO-211H and MMP cells respectively (the unit may be damaged in this copy), with minimal toxicity in the normal cells. The drug reduced activation of a protein called AKT. In REN cells it halted the cell cycle at the G2/M phase without evident apoptosis, and all cells exposed to 23 mM died by 72 hours. Permanently active forms of AKT1 and AKT3 reversed the growth block. Perifosine also blocked activation of the EGFR and MET receptors. With cisplatin it showed strong synergy in REN cells. It was additive with gemcitabine and seemed to antagonize pemetrexed. The authors concluded their results underline perifosine as a multi-target therapy for mesothelioma, but said the cisplatin combination must be validated by in vivo studies.

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 (in vitro) experiment on human mesothelioma cell lines and normal mesothelial cells
• Who was studied: Cell lines, not people, studied at Italian institutions (Novara and Vercelli). The mesothelioma cell lines were REN (epithelioid, the main model), MSTO-211H (biphasic) and MMP (established from pleural effusions of malignant mesothelioma patients). Normal mesothelial cells (HMC-TERT) came from patients with congestive heart failure and were immortalized. A549 cells were used as a comparison in AKT gene-expression tests.
• Exposure: No asbestos exposure was studied. Cells were treated with the drug perifosine alone, after stimulation with the growth factors EGF or HGF, and in combination with cisplatin, pemetrexed or gemcitabine for 24 hours. Concentrations are as printed; the unit symbols may be damaged.
• Main results:
  • After 24 hours, the perifosine concentration causing 50% growth inhibition was printed as 23 mM for REN, 14 mM for MSTO211H and 7.5 mM for MMP mesothelioma cells. Minimal toxicity was seen in HMC normal mesothelial cells.
  • In the mesothelioma cell lines, 1 hour of perifosine caused a dose-dependent loss of AKT activation (Ser473 phosphorylation) without changing the total amount of AKT protein.
  • In REN cells, 24 hours of perifosine caused cell cycle arrest with accumulation in the G2/M phases. No caspase-dependent apoptotic cell death was evident at 24 hours.
  • The effect grew with time: all REN cells exposed to 23 mM perifosine had died by 72 hours.
  • REN cells expressed AKT1 and AKT3; AKT2 mRNA was not detected.
  • In REN cells, introducing permanently active (myristoylated) AKT1 or AKT3 rescued the perifosine-induced block of cell proliferation.
  • In REN cells pre-treated with perifosine, the EGFR and MET receptors were not activated (phosphorylated) even when their growth factors EGF or HGF were added.
  • In REN cells, perifosine combined with cisplatin showed strong synergistic toxicity across a broad range of doses.
  • In REN cells, perifosine had an additive effect with gemcitabine and seemed to antagonize the effect of pemetrexed.
• The authors' conclusion: The authors concluded that their results underline perifosine as a multi-target therapy for malignant pleural mesothelioma. They added that the cisplatin combination still needs validation in further in vivo studies.
• Limitations the authors state:
  • The benefit of combining cisplatin and perifosine was shown only in cells and must be validated by further in vivo studies.
  • Further study of how the AKT forms function in mesothelioma is needed.

Topics

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

Medical terms in this study, explained in our Lexicon: EGFR, Pleural Mesothelioma, Clinical Trial, Mesothelial Cells, Mesothelioma, Cisplatin.

Related studies

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• Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells — M. Yamaji, A. Ota, et al. (2017)
• Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma — W.B. Ou, C. Hubert, et al. (2011)
• Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells — K. Kawaguchi, H. Murakami, et al. (2009)
• Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy — M. Brevet, S. Shimizu, et al. (2011)
• Gefitinib targets EGFR dimerization and ERK1/2 phosphorylation to inhibit pleural mesothelioma cell proliferation — R.E. Favoni, A. Pattarozzi, et al. (2010)

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