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Open AccessArticle

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

1
Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland
3
Institute of Pathology, University of Bern, 3008 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2019, 11(10), 1502; https://doi.org/10.3390/cancers11101502
Received: 25 July 2019 / Revised: 20 September 2019 / Accepted: 22 September 2019 / Published: 8 October 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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. View Full-Text
Keywords: malignant pleural mesothelioma (MPM); endoplasmic reticulum (ER) stress; unfolded protein response (UPR); HA15; autophagy malignant pleural mesothelioma (MPM); endoplasmic reticulum (ER) stress; unfolded protein response (UPR); HA15; autophagy
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Xu, D.; Yang, H.; Yang, Z.; Berezowska, S.; Gao, Y.; Liang, S.-Q.; Marti, T.M.; Hall, S.R.R.; Dorn, P.; Kocher, G.J.; Schmid, R.A.; Peng, R.-W. Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma. Cancers 2019, 11, 1502.

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