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, Robert; Moréra, Solange; Vigouroux, Armelle; Gual, Philippe; Ali, Maruf M. U.; Bertolotto, Corine; Hofman, Paul; Ballotti, Robert; Benhida, Rachid; Rocchi, Stéphane

doi:10.1016/j.ccell.2016.06.007

Cited by 42 publications

(28 citation statements)

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“…Cerezo et al (30) reported on the development of the small molecule HA15 that displayed antitumor activity in both BRAF-mutant and NRAS-mutant melanoma cell lines and in melanoma xenograft mouse models. HA15 appears to interact directly with the chaperone protein GRP78, leading to melanoma cell death by significantly increasing ER stress and activating the UPR.…”

Section: Discussionmentioning

confidence: 99%

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BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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Purpose NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected. Experimental design and results BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process. Conclusion The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, HA15 induced both apoptosis and autophagy, culminating in cell death that could be blocked by QVD and siRNA against the autophagy protein LC3 (30). In our system, BRAFi alone was not capable of inducing apoptosis in NRAS-mutant melanoma.…”

Section: Discussionmentioning

confidence: 99%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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“…Furthermore, in human PDAC cell lines, GRP78 has been reported to promote proliferation, migration, invasion, viability, and chemoresistance (14,25,27,28). Thus, the utility of inhibitors of GRP78 expression in combating PDAC and chemoresistance merits further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, GRP78 was upregulated in ductal structures of both human and murine ADM and PDAC lesions and colocalized with activated AKT on the cell surface (26). In human PDAC cell lines, knockdown of GRP78 or treatment of the cells with anti-GRP78 agents resulted in decreased proliferation, invasion, viability, and chemoresistance, suggesting that suppression of GRP78 could represent a novel approach to combat human mutant KRAS-driven PDAC (14,25,27,28).…”

mentioning

confidence: 99%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras G12D/+ ;p53 f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78 f/+ allele (PKC78 f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78 f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78 f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78 f/+ and c78 f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.glucose-regulated protein 78 | GRP78 | pancreatic ductal adenocarcinoma | acinar-to-ductal metaplasia | Kras P ancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases with limited therapeutic options and an overall 5-y survival rate of <10%; therefore, identification of targetable key players in tumor initiation as well as tumor maintenance is urgently needed (1). PDAC is believed to arise from a range of preneoplastic mucinous lesions with ductal morphology, pancreatic intraepithelial neoplasia (PanIN) being the most common in humans (2). About 90% of PDAC contains activating mutations of KRAS whereas 50-75% contain mutations in Tp53 (1). Mutationally activated oncogenic KRAS signals through the PI3K-PDK1-AKT pathway and the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2, as well as via positive feedback activation of receptor tyrosine kinases engaged by autocrine and paracrine stimuli (3). Although the histological appearance of PDAC suggests a ductal cell of origin, accumulating evidence reveals that PDAC originates primarily through transdifferentiation of acinar cells into ductal cells in a process referred to as acinar-to-ductal metaplasia (ADM), although centroacinar cells and pancreas precursor cells could also give rise to PDAC (2, 4, 5). To study PDAC, a pancreatic cancer mouse model mimicking human PDAC has been established using the pancreatic...

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“…This explains why therapeutic strategies that increase MITF expression, such as the use of methotrexate, can be highly effective at preventing metastatic spread (Saez-Ayala et al 2013). More importantly, our discovery that translation reprogramming can repress MITF has significant implications for therapeutic use of drugs that deliberately (Cerezo et al 2016) or inadvertently up-regulate ER stress and ATF4 in melanoma. Nelfinavir, identified recently in a drug-repurposing screen as a melanoma therapeutic that down-regulates MITF , is known to inhibit an eIF2α phosphatase (De Gassart et al 2016), and, while reported to down-regulate MITF via suppression of PAX3, we show that nelfinavir can also promote translation reprogramming and ATF4 expression in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

et al. 2017

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The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammationmediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.

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

Cited by 42 publications

References 0 publications

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

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