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

Our plain-English summary of Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma, by D. Xu, H. Yang, Z. Yang, et al (Cancers, 2019).

The study

• Authors: D. Xu, H. Yang, Z. Yang, S. Berezowska, Y. Gao, S.Q. Liang, T.M. Marti, S.R.R. Hall, P. Dorn, G.J. Kocher, R.A. Schmid, R.W. Peng
• Journal: Cancers
• Published: 2019;11(10)
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a laboratory study, not a study of asbestos exposure. The authors analysed public gene-expression data from malignant pleural mesothelioma (MPM) tumors. They then tested HA15, a drug that increases endoplasmic reticulum (ER) stress in cells, in cell cultures and in mice. In the public data, genes of the ER stress response (the unfolded protein response, UPR) were more active in tumors than in normal lung or pleura tissue. In a TCGA group of 86 patients, a higher UPR gene score was associated with poorer survival. In the laboratory, HA15 reduced the survival of MPM cell lines and of a tumor culture from one patient, with 50% inhibitory concentrations from 5.71 to 20.51 µM. It only mildly affected normal lung fibroblasts and normal mesothelial cells. It also acted on MPM cells that had been made resistant to cisplatin/pemetrexed. In mice carrying tumors grown from one patient's cells (4 mice per group), HA15 had a greater anti-tumor effect than chemotherapy, with no obvious side effects. The authors concluded that their results support further investigation of HA15 as a treatment for MPM. They noted that its effects on immunity have not yet been studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (preclinical) study: analysis of public tumor gene-expression and survival data, cell culture experiments, and a mouse experiment using tumors grown from a patient's cells (patient-derived xenograft)
• Who was studied: Public gene-expression data on MPM tumors, including a TCGA survival cohort of 86 MPM patients. MPM cell lines (MESO-1, MESO-4, H28, JL-1, MSTO-211H, H2052), a primary MPM culture (BE261T) from a 67-year-old male patient in Bern, normal lung fibroblasts (hFb16lu) and normal mesothelial cells (Met-5A). Immune-deficient NSG mice, 4 per group.
• Exposure: No asbestos exposure was studied. The exposure was the experimental drug HA15, which targets the protein BiP to cause excess ER stress. In mice it was given at 0.7 mg per mouse, 5 days a week for five weeks, and compared with cisplatin (3.75 mg/kg) plus pemetrexed (83 mg/kg) once weekly.
• Main results:
  • In public data, ER stress and UPR genes were significantly enriched in MPM tumors compared with normal lung/pleura tissue
  • In the TCGA cohort of MPM patients (n = 86), a higher UPR gene signature was associated with poor prognosis
  • The protein BiP was generally overexpressed in MPM cell lines, except H28, which had a lower BiP level than normal mesothelial Met-5A cells
  • In MPM cells, HA15 had 50% inhibitory concentrations (IC50) of 5.71 to 20.51 µM. It only mildly affected the normal Met-5A and hFb16lu cells.
  • In MESO-1 cells, reducing the protein CHOP significantly weakened HA15's growth-inhibiting, cell-death and autophagy effects
  • Both chemotherapy-resistant MPM cells and the original (parental) cells responded to HA15 in a dose-dependent manner
  • In mice with patient-derived (BE261T) tumors, HA15 at the dose used had a greater anti-tumor effect than chemotherapy
  • HA15-treated mice showed no obvious side effects, judged by body weight, liver histology and liver enzyme tests. The authors stated that the chemotherapy's efficacy came at the cost of high toxicity.
• The authors' conclusion: The authors concluded that disturbed ER stress/UPR signaling is a characteristic feature of MPM. They concluded that this supports further investigation of HA15 as a novel therapy for MPM patients.
• Limitations the authors state:
  • The authors stated that the potential side effects of HA15 on immunity remain to be addressed. The mouse experiments used immune-deficient NSG mice.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Targeted Therapy, Chemotherapy.

Related studies

• Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma — D. Xu, S.Q. Liang, et al. (2018)
• MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma — H. Yang, Y. Gao, et al. (2023)
• CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma — D. Xu, S.Q. Liang, et al. (2020)
• Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death — S. Nozaki, G.W. Sledge, et al. (2001)
• The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma — L.E. Dalton, H.J. Clarke, et al. (2013)
• Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response — D.W. Kamp, G. Liu, et al. (2013)

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