HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target

Fok, Jacqueline H. L.; Hedayat, Somaieh; Zhang, Lei; Aronson, Lauren I.; Mirabella, Fabio; Pawlyn, Charlotte; Bright, Michael D.; Wardell, Christopher P.; Keats, Jonathan J.; Billy, Emmanuel de; Rye, Carl S.; Chessum, N.; Jones, Keith; Morgan, Gareth J.; Eccles, Suzanne A.; Workman, Paul; Davies, Faith E.

doi:10.1158/1078-0432.ccr-17-1594

Cited by 48 publications

(39 citation statements)

References 47 publications

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“…The fact that the MM.1S and MM.1R lines responded differently to MEK inhibition was an interesting finding as these are both derived from the MM.1 line, with the key difference being the latter lacking a GR, raising the potential for convergence between GR-mediated and RAS-MAPK signalling [26]. Therefore, we confirmed target engagement of both trametinib and dexamethasone using known pharmacodynamic biomarkers phospho-ERK1/2 [18] and FKBP5 [27] in MM.1S and MM.1R cells (Fig. 1c).…”

Section: Ras-mutant Myeloma Cell Lines Demonstrate Differential Sensisupporting

confidence: 52%

Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma

et al. 2020

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Background: Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RASmutant MM. Methods: The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time. Results:The Tra/Dex combination demonstrated synergistic cytotoxicity in KRAS G12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth.Conclusions: Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.The combination of the MEK inhibitor trametinib and dexamethasone exhibits antiproliferative activity in models of RAS-mutant multiple myeloma. Suppression of PDK1 signalling is identified as a potential biomarker of response.

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Section: Ras-mutant Myeloma Cell Lines Demonstrate Differential Sensisupporting

confidence: 52%

Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma

et al. 2020

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“…Furthermore, because HSP47 acts as a universal molecular chaperone for collagen, they proposed that inhibition of HSP47 could be a good candidate for controlling tissue fibrosis [52]. Conversely, several studies have showed an unexpected pro-oncogenic role of HSF1 [53, 54]. HSF1 remains latent in primary cells without stress, it becomes constitutively activated within malignant cells, rendering them addicted to HSF1 for their growth and survival.…”

Section: Discussionmentioning

confidence: 99%

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

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et al. 2020

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Loss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β -galactosidase activity (SA-β-gal) staining, the DNA damage marker γ H2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1 ser307 and HSF1 K298 sumo , downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H 2 O 2 showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis. METHODSAnimals. C57B/6J mice (8-10 weeks old) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed in a pathogen-free animal facility at Thomas Jefferson University. Throughout the study period, mice were maintained on a standard chow diet (13.5% calories from fat, 58% from carbohydrates, and 28.5% from protein) and permitted to feed ad libitum. ). They were isolated from the uninvolved periphery of the organ of six lung cancer patients. Fresh tissues were transported immediately to the laboratory for isolating fibroblasts according to procedures described before [35].Bleomycin-induced lung injury: Bleomycin sulphate (Enzo life science, BML-AP302-0050) was dissolved in phosphate buffered saline. Lung injury was induced by instilling 0.04U of bleomycin into the posterior oropharynx of anesthetized mice every other week for five doses [36]. The mice were observed following intubation to ensure complete recovery from anesthesia. Mice were euthanized 2 weeks after the last dose by exposure to carbon dioxide, and lungs were harvested for fibroblast isolation and histological preparation...

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“…Therefore, a lot of efforts have been made to develop inhibitors that could target both chaperones. To this aim, CCT251236 or KRIBB11, novel Heat Shock Factor 1 (HSF1) inhibitors, have shown cytotoxic effects in MM cells, via induction of UPR, with altered EIF2α phosphorylation, CHOP expression and a reduction in protein synthesis (78). Thus, chaperone targeting seems a promising approach for the treatment of MM.…”

Section: Targeting Mm-associated Anomalies In Molecules Involved In Tmentioning

confidence: 99%

Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From “Omics” Research

et al. 2020

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While the modern therapeutic armamentarium to treat multiple myeloma (MM) patients allows a longer control of the disease, this second-most-frequent hematologic cancer is still uncurable in the vast majority of cases. Since MM plasma cells are subjected to various types of chronic cellular stress and the integrity of specific stress-coping pathways is essential to ensure MM cell survival, not surprisingly the most efficacious anti-MM therapy are those that make use of proteasome inhibitors and/or immunomodulatory drugs, which target the biochemical mechanisms of stress management. Based on this notion, the recently realized discoveries on MM pathobiology through high-throughput techniques (genomic, transcriptomic, and other "omics"), in order for them to be clinically useful, should be elaborated to identify novel vulnerabilities in this disease. This groundwork of information will likely allow the design of novel therapies against targetable molecules/pathways, in an unprecedented opportunity to change the management of MM according to the principle of "precision medicine." In this review, we will discuss some examples of therapeutically actionable molecules and pathways related to the regulation of cellular fitness and stress resistance in MM.

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HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target

Cited by 48 publications

References 47 publications

Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma

Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From “Omics” Research

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