MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial

Abstract

BACKGROUND: 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. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. METHODS: Promoter 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. RESULTS: STK4 (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. CONCLUSIONS: MST1/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.

Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide

“…As shown in Figure2K, compared with the DMSO treated group, YAP nuclear level decreased, while increased in cytoplasm after imipramine treatment. Furthermore, by using cellular fractionation and immunoblotting, we got similar results in both cells (Figure2L,M).Since YAP is a key effector molecule downstream of Hippo signalling pathway,32,33 we wondered whether the regulation of YAP by imipramine is Hippo-dependent. Therefore, both the mRNA and protein levels of YAP direct upstream kinases, such as MST andLATS, were determined by qRT-PCR and Western blot analysis after imipramine treatment.…”

“…Since YAP is a key effector molecule downstream of Hippo signalling pathway, 32 , 33 we wondered whether the regulation of YAP by imipramine is Hippo‐dependent. Therefore, both the mRNA and protein levels of YAP direct upstream kinases, such as MST and LATS, were determined by qRT‐PCR and Western blot analysis after imipramine treatment.…”

Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

“…Several miRNAs have also been reported to control the levels of LATS1/2 (Lee et al, 2009). Promoter hypermethylation has also been reported for MST1/2 (Steinmann et al, 2009;Maille et al, 2019). MORC2 (microrchidia) acts as a negative regulator of Hippo signaling.…”

Pathologic Considerations and Standardization in Mesothelioma Clinical Trials

“…113,114 The Hippo mammalian sterile 20-like kinase (MST1) regulates Yes-associated protein (YAP) through large tumor suppressor homologue 1/2 (LATS1/2) kinases, and its methylation has been associated with poor survival outcomes in mesothelioma. 115 YAP may also have immunologic relevance since its expression is strongly correlated with PD-L1. 116 Novel methodologies and therapeutic opportunities will lead to investigations of tumor markers that have not specifically been covered in this review.…”