Abstract
BackgroundThe Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.MethodsPromoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.ResultsSTK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09–2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.ConclusionsMST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
Highlights
The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients
MST1 promoter hypermethylation predicts shorter overall survival (OS) of MPM patients Assessing the baseline characteristics of patients from the MAPS trial reveals that biological parameters, general status (PS 0–1 versus >2), and histology are potent prognostic factors of OS (p < 0.05) and progression-free survival (PFS) in univariate and multivariate analyses (2) in this subset of MAPS patients
While MST1 inactivation had not previously been evidenced in MPM, our findings are in line with the reports of frequent genetic alterations of Hippo pathway members recently revealed in MPM23 and support the concept that Hippo pathway alterations are key events in pleural carcinogenesis.[23,27,28]
Summary
The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. Malignant pleural mesothelioma (MPM) is a rare yet aggressive cancer with poor prognosis mainly caused by occupational asbestos exposure.[1] Recently, the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) demonstrated the benefit of bevacizumab plus cisplatin/pemetrexed doublet combination on both overall (OS) and progression-free survival (PFS) in 448 MPM patients.[2] Following this trial, a biological study (Bio-MAPS) is currently evaluating new biomarkers, including the Hippo mammalian sterile 20-like kinase (MST1), as MPM has recently been proven to harbour frequent Hippo pathway alterations.[3]. Inactive/phosphorylated YAP/TAZ are sequestered in the cytoplasm by proteins such as 14.3.3 or betacatenin, while active/dephosphorylated YAP/TAZ interact with numerous transcription factors and cause transcription of genes
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