Drug development against the hippo pathway in mesothelioma

Woodard, Gavitt A.; Yang, Yilin; Li, You; Jablons, David M.

doi:10.21037/tlcr.2017.06.02

Cited by 28 publications

(30 citation statements)

References 56 publications

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“…Two MPM cell lines, H2052 and 211H, showed increased PD‐L1 protein expression and significantly increased PD‐L1 mRNA expression. We previously reported that YAP is frequently activated in human MPM and suggested YAP as a potential therapeutic target 20, 21. Our current study shows that inhibition of YAP down‐regulates PD‐L1 expression in H2052 and 211H cells.…”

Section: Discussionsupporting

confidence: 58%

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

Hsu

Miao

Wang

et al. 2018

J Cellular Molecular Medi

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Although tumour PD‐L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD‐L1 axis in various cancers, the regulation of PD‐L1 (CD274) expression is unclear. Yes‐associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down‐regulates PD‐L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD‐L1 protein expression compared to H290, MS‐1 and H28 cells. In H2052 and 211H cells, PD‐L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD‐L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD‐L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD‐L1 enhancer region encompassing 2 putative YAP‐TEAD‐binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD‐L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi‐square). We conclude that PD‐L1 is correlated with YAP expression, and inhibition of YAP down‐regulates PD‐L1 expression in human MPM. Further study of how YAP regulates PD‐L1 in MPM is warranted.

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Section: Discussionsupporting

confidence: 58%

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

Hsu

Miao

Wang

et al. 2018

J Cellular Molecular Medi

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“…Today, there is still no oncogenic “driver” identified in MPM enabling targeted therapeutics to be developed. 24 To identify such a putative driver, the Bio-MAPS study set out to characterise the molecular abnormalities in tumours from patients enroled in the MAPS phase 3 trial. Focusing on Hippo pathway alterations, we assayed MST1 gene promoter hypermethylation, for the first time to our best knowledge, in a subset (8.5%) of MPM patients.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…Hippo monitors external factors that shape tissue structure (25). NF2 recruits core Hippo signalling pathway members (LATS1/2) to inhibit activation of the transcriptional cofactors YAP1 and TAZ (26).…”

Section: Hippo Signallingmentioning

confidence: 99%

Integrated genomics identify novel immunotherapy targets for malignant mesothelioma

Năstase

Mandal

et al. 2020

Preprint

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Malignant pleural mesothelioma (MPM) is an aggressive malignancy that lacks effective therapy. To identify therapeutic targets we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised losses of SUFU, observed in 21% of 118 tumours, resulted in disordered expression of Hedgehog pathway transcripts and genes from the T-cell synapse, including VISTA. Co-deletion of Interferon type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. The results indicate multiple new therapeutic avenues in MPM and include targets and biomarkers for immunotherapy.

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Drug development against the hippo pathway in mesothelioma

Cited by 28 publications

References 56 publications

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

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

Integrated genomics identify novel immunotherapy targets for malignant mesothelioma

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