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.
Highlights
Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer [1,2], consisting of epithelioid, mixed and sarcomatoid histological subtypes [3]
We showed that deregulation of endoplasmic reticulum (ER) stress/unfolded protein response (UPR) signaling is a hallmark of MPM, which confers a specific vulnerability of therapeutic potential
Gene enrichment set analysis (GESA) revealed that genes involved in ER stress and the adaptive UPR (UPR gene signature) were significantly enriched in the patients’
Summary
Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer [1,2], consisting of epithelioid, mixed (biphasic) and sarcomatoid histological subtypes [3]. Whereas aggressive surgery is amenable for early-stage tumors [5], a majority (80%) of patients with MPM are diagnosed at advanced stages, for which a dual chemotherapy regimen that combines cisplatin and pemetrexed is the only clinically approved therapy [6]. This systemic treatment only mildly improves patient survival (by three months only), as drug resistance, de novo, and/or acquired after the treatment, prevails [7]. The lack of druggable activating mutations [9,11,12] have significantly hampered the development of targeted therapies for MPM, which, suggests the importance of identifying and targeting functional cancer dependencies rather than specific driver mutations to combat MPM
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