The PI3K/AKT signaling pathway is aberrantly active and may have an important biologic impact in malignant pleural mesothelioma cell cycle progression and chemo-resistance. Moreover, the EGFR family, EGFR, ErbB2 or ErbB3, is frequently co-activated with MET, suggesting that MET and EGFR may compensate for each other in activating downstream signals. Perhaps because of these multiple active pathways, single receptor tyrosine kinase (RTK) inhibitors are generally not sufficient to inhibit mesothelioma cell proliferation and inhibition of multiple RTKs may be needed for a more effective therapy.
The authors in this study focused on the PI3K/PDK1/AKT signaling pathway as a potential target for mesothelioma therapy, because it is a point of convergence for growth factor-related effects on cell proliferation. They investigated the activity of perifosine, a novel synthetic alkylphospholipid Akt inhibitor (as a single agent and together with chemotherapy) on the proliferation and survival of mesothelioma cell lines. Alkylphospholipids (ALP) are a new class of antitumor agents which target the cell membranes of actively proliferating cells and inhibit PH domain-mediated AKT membrane recruitment and activation.
The authors demonstrate that perifosine, currently being evaluated as an anti-cancer agent in phase I and II clinical trials, causes a dose-dependent reduction of AKT activation and MMe cell growth arrest. They found that mesothelioma cells express AKT1 and AKT3 and that either of the myristoylated and constitutively active forms of Akt abrogated perifosine-mediated cell growth inhibition. The perifosine also acted synergistically in combination with cisplatin. Interestingly, the perifosin also appeared to interfere with the phosphorylation of the upstream kinases, EGFR and MET.
This study suggests that perifosine acts in a novel way to inhibit the EGFR/MET/AKT axis and proposes perifosine as a potential multi-target therapy for mesothelioma.
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