Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance

Cerezo, Michaël; Lehraiki, Abdelali; Millet, Antoine; Rouaud, Florian; Plaisant, Magali; Jaune, Emilie; Botton, Thomas; Ronco, Cyril; Abbe, Patricia; Amdouni, Hella; Passeron, Thierry; Hofman, Véronique; Mograbi, Baharia; Dabert-Gay, Anne-Sophie; Debayle, Delphine; Alcor, Damien; Rabhi, Nabil; Annicotte, Jean-Sébastien; Héliot, Laurent; Gonzalez-Pisfil, Mariano; Robert, Caroline; Moréra, Solange; Vigouroux, A.; Gual, Philippe; Ali, Maruf M. U.; Bertolotto, Corine; Hofman, Paul; Ballotti, Robert; Benhida, Rachid; Rocchi, Stéphane

doi:10.1016/j.ccell.2016.04.013

Cited by 191 publications

(186 citation statements)

References 44 publications

(49 reference statements)

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“…These data support the biological relevance of the target, but further studies are needed to explore dose and regimen before this pharmacological agent can be translated into human adjuvant trials that target metastatic progression. It would be worthwhile to assess whether other GRP78-targeting chemical compounds such as HA15 [34] and medicarpin [35] have antimetastatic effects. Bioconjugates such as Mab159 [36] and BMTP78 [37] that target GRP78 have been shown to have antimetastatic effects.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression

et al. 2016

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Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies.

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Section: Discussionmentioning

confidence: 99%

Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression

et al. 2016

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“…ER stress-induced autophagy can also be highly cytotoxic, as was recently shown with the BiP inhibitor HA15. This compound induced apoptosis in a variety of chemoresistant cancer cell lines in vitro and in vivo , though the mechanism remains incompletely understood (Cerezo et al, 2016). In sum, optimal cancer growth and survival relies on carefully balanced UPR signaling pathways that interact with other cell processes such as autophagy, to result in cancer cell death or survival.…”

Section: Mechanisms Of Er Stress-mediated Tumor Progressionmentioning

confidence: 99%

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer

Cubillos-Ruiz

Bettigole²,

Glimcher

2017

Cell

664

566

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SUMMARY Malignant cells utilize diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting the development of anti-tumor immune responses. Hostile microenvironmental conditions within tumor masses, such as nutrient deprivation, oxygen limitation, high metabolic demand and oxidative stress disturb the protein folding capacity of the Endoplasmic Reticulum (ER), thereby provoking a cellular state of “ER stress”. Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic and drug resistant capacity. Additionally, recent studies have uncovered that ER stress responses further impede the development of protective anti-cancer immunity by manipulating the function of myeloid cells in the tumor microenvironment. Here, we discuss the tumorigenic and immunoregulatory effects of ER stress in cancer, and we explore the concept of targeting ER stress responses to enhance the efficacy of standard chemotherapies and evolving cancer immunotherapies in the clinic.

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“…Furthermore, in certain tumors such as melanoma, the most effective strategy for exploiting ER stress would most likely involve the combination of agents that inhibit cytoprotective function of UPR arms along with those that actively induce ER stress/response (64)(64). The second approach is to pharmacologically increase ER stress above a certain threshold in cells that already have a high dependency on the UPR, thereby triggering cell death (65). For instance, Cerezo et al reported the development of the small molecule HA15 belonging to the thiazole benzensulfonamides.…”

Section: The Upr Presents Multiple Potential Drug Targetsmentioning

confidence: 99%

Targeting the unfolded protein response in cancer

Ojha

Amaravadi

2017

Pharmacological Research

102

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Cancer cells are exposed to various intrinsic and extrinsic factors that disrupt protein homeostasis, producing endoplasmic reticulum (ER) stress. To cope with these situations, cancer cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR) to restore the ER homeostasis. Recently, several pharmacological agents have been found to exhibit anti-tumor activity by targeting the UPR components. The development of potent and specific compounds that target the UPR components has not only shed light on the regulation of the UPR in cancer cells, but also brought the field closer to clinical drug candidates. Here we present an overview of the milestones in the field of UPR biology in cancer with a focus on new strategies for pharmacological inhibition.

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Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance

Cited by 191 publications

References 44 publications

Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression

Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer

Targeting the unfolded protein response in cancer

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