Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018)

Wu, Licun; Dell’Anno, Irene; Lapidot, Moshe; Sekido, Yoshitaka; Chan, Man Khun; Kohno, Mikihiro; Serre‐Beinier, Véronique; Felley‐Bosco, Emanuela; Perrot, Marc de

doi:10.1016/j.lungcan.2018.11.034

Cited by 12 publications

(10 citation statements)

References 63 publications

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“…Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy that is etiologically associated with asbestos exposure 1,2 . Despite the restriction of asbestos use in most countries, the incidence of MPM is still rising due in part to the long latency (around 40 years) of the interval from carcinogen exposure to tumor onset 3 . There are no typical clinical symptoms of mesothelioma in the early phase, and the majority of patients (80%) are diagnosed at advanced stages associated with extremely poor prognosis 4 .…”

Section: Introductionmentioning

confidence: 99%

Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

Liang

Zhang

et al. 2021

Cell Death Dis

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Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients’ tumors, we identified BCL-XL as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-XL-selective BH3 mimetic. Importantly, BCL-XL inhibition elicits protective autophagy, and concomitant blockade of BCL-XL and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease.

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Section: Introductionmentioning

confidence: 99%

Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

Liang

Zhang

et al. 2021

Cell Death Dis

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“…Comprehensive genomic studies revealed that MPM is predominantly driven by loss of function mutations in tumor suppressor genes, most commonly the cyclin-dependent kinase inhibitor 2A/2B gene ( CDKN2A/2B ), BRCA1 associated protein 1 gene ( BAP1 ), neurofibromin 2 gene ( NF2 ), whereas therapeutically tractable oncogenic drivers are rare [8,9,10]. The lack of druggable activating mutations [9,11,12] have significantly hampered the development of targeted therapies for MPM, which, however, suggests the importance of identifying and targeting functional cancer dependencies rather than specific driver mutations to combat MPM.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma

Yang

Zhang

et al. 2019

Cancers

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Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, naïve or resistant to chemotherapy.

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“…Attempts to exploit this pathway for diagnostic purposes have, thus far, had limited success (see Discussion). Aberrant functioning of the Hippo pathway leads, among other things, to overproduction of cyclin D1 (see Discussion) [8,9]. Here we show that immunostaining for cyclin D1 can be used in the separation of benign from malignant mesothelial processes.…”

Section: Introductionmentioning

confidence: 61%

“…One of the recurring genetic abnormalities in malignant mesothelioma is mutation or deletion of genes in the Hippo signaling pathway [7][8][9][10]. Attempts to exploit this pathway for diagnostic purposes have, thus far, had limited success (see Discussion).…”

Section: Introductionmentioning

confidence: 99%

Cyclin D1 immunohistochemical staining to separate benign from malignant mesothelial proliferations

et al. 2020

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The separation of benign from malignant mesothelial proliferations is a morphologically difficult problem. Mutations/ deletions of components of the Hippo pathway are frequent in malignant mesotheliomas, and one downstream effect of aberrant Hippo signaling is increased production of cyclin D1. We examined expression of cyclin D1 nuclear staining in two tissue microarrays containing 52 reactive epithelial mesothelial proliferations, 51 reactive spindle cell mesothelial proliferations, 54 epithelial mesotheliomas, and 22 sarcomatous/desmoplastic mesotheliomas. When present, cyclin D1 staining was always strong, hence the arrays were scored as 0, 1-25%, 26-50%, 51-75%, and 76-100% staining. Both arrays showed a similar pattern. Reactive epithelial proliferations generally showed no staining (42/52 cases) or 1-25% staining (10/52 cases) with no cases showing >25% staining. Overall for reactive epithelial proliferations the maximum staining was 14.8% and mean 1.1 ± 2.9%. For epithelial mesotheliomas 39/54 (72%) cases demonstrated >25% staining, with 8/54 in the 26-50% staining range, 9/54 in the 51-75% range, and 22/54 in the >75% range. Combinations of staining using cyclin D1 >50% plus BAP1 or MTAP loss in epithelial mesotheliomas produced about a 10% increase in sensitivity. Reactive spindle cell proliferations showed a broader range of staining with 27/51 in the 1-25% range, 5/51 in the 26-50% range, and 1/51 >50%. Eleven of 22 sarcomatous/desmoplastic mesotheliomas scored 50% or greater. We conclude that for epithelial mesothelial proliferations, the finding of >50% of tumor cells staining supports a diagnosis of epithelial mesothelioma with 100% specificity but only modest (57%) sensitivity.

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Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018)

Cited by 12 publications

References 63 publications

Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma

Cyclin D1 immunohistochemical staining to separate benign from malignant mesothelial proliferations

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