Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Cristea, Sandra; Sage, Julien

doi:10.1016/j.jtho.2016.04.018

Cited by 42 publications

(39 citation statements)

References 73 publications

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“…These signaling pathways enriched for common downstream kinases ( MAPK1 , MAPK3K1 , MAP3K2 , MAPK8 , MAPK11 , MAPAPK2 , PRKCA , PRKCD , PRKCE , PRKCZ ). As EGF, FGF, Ras, Hedgehog and other of these signaling pathways converge upon MAPK/ERK and mTOR signaling (Cristea & Sage 2016; Switon et al 2016; Kim et al 2016; McCubrey et al 2016), we hypothesized that targeting these downstream pathways may be an effective way to simultaneously disrupt multiple oncogenic pathways. Cell viability was disrupted in two out of four cell-cultures when treated with ERK1/2 inhibitor SCH772984 (Morris et al 2013) and all four cell-cultures with dual mTORC1/2 inhibitor AZD8055 (Chresta et al 2010) at sub-micromolar concentrations (AZD8055: median IC 50 0.12 mM; Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

et al. 2017

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Summary Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

et al. 2017

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“…Thus, SDC2 induces migration by activating the FAK/PI3K/Tiam1/Rac signalling pathway, possibly leading to subsequent actin remodelling, but independent of integrin‐α2, α5 and β1 participation . An additional pathway through which SDC2 induces important intracellular signals is the phosphorylation of extracellular signal‐regulated kinase (ERK1/2) , a kinase known to affect cell growth and differentiation, adhesion, migration, proliferation, survival and apoptosis . Interestingly, in fibrosarcoma, SDC2 expression seems to be controlled by another member of the HSPG family, SDC1, which uses SDC2 to enhance HT1080 cell chemotaxis .…”

Section: Role Of Sdc2 In Cancermentioning

confidence: 99%

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

et al. 2017

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Syndecan 2 (SDC2) belongs to a four-member family of evolutionary conserved small type I transmembrane proteoglycans consisting of a protein core to which glycosaminoglycan chains are covalently attached. SDC2 is a cell surface heparan sulfate proteoglycan, which is increasingly drawing attention for its distinct characteristics and its participation in numerous cell functions, including those related to carcinogenesis. Increasing evidence suggests that the role of SDC2 in cancer pathogenesis is dependent on cancer tissue origin rendering its use as a biomarker/therapeutic target feasible. This mini review discusses the mechanisms, through which SDC2, in a distinct manner, modulates complex signalling networks to affect cancer progression. © 2017 IUBMB Life, 69(11):824-833, 2017.

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“…SCLC tumors have very few activating events in genes coding for kinases (reviewed in ref. 11). Nevertheless, work on kinases implicated in the response to DNA damage, including WEE1 and CHK1 (12)(13)(14), shows that such kinases are promising targets in this disease.…”

Section: Introductionmentioning

confidence: 99%

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

et al. 2020

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Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. Significance: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.

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Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Cited by 42 publications

References 73 publications

Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

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