MEK in cancer and cancer therapy

Neuzillet, Cindy; Tijeras‐Raballand, Annemilaï; Mestier, Louis de; Cros, Jérôme; Faivre, Sandrine; Raymond, Éric

doi:10.1016/j.pharmthera.2013.10.001

Cited by 208 publications

(189 citation statements)

References 127 publications

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“…The TGF-β pathway involves the Smad protein family (27). These proteins play an important role in triggering diseases including for example fibrosis (28) and cirrhosis, leading to HCC (29). NDRG1 overexpression could inhibit TGF-β-induced effects via reducing both Smad2 and Smad3 expression (63).…”

Section: Discussionmentioning

confidence: 99%

“…Pathways involving Smad family members are also important regulators (27). Such proteins are crucial for the pathophysiological regulation and involved in the development of various diseases including fibrosis (28) and cirrhosis, leading to HCCs (29). Particularly, one member of the Smad family, Smad7, abrogates the TGF-β1 signaling pathway by initiating a negative feedback loop (30).…”

Section: Time-and Oxygen-dependent Expression and Regulation Of Ndrg1mentioning

confidence: 99%

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Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

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Abstract. N-myc downstream-regulated gene 1 (NDRG1) is a tumor suppressor with the potential to suppress metastasis, invasion and migration of cancer cells. It is regulated under stress conditions such as starvation or hypoxia. NDRG1 regulation is both induced and controlled by HIF-1α-dependent and -independent pathways under hypoxic conditions. However, there are profound differences in the way NDRG1 expression is regulated by HIF-1α and other transcription factors. Therefore, we aimed to define the time-dependent pattern of NDRG1 mRNA and protein expression in human glioblastoma cell lines in extreme hypoxia and after re-oxygenation as well as under normoxic conditions. Furthermore, we ascribe the regulation of NDRG1 to the transcription factors HIF-1α, SP1, CEBPα, YB-1 and Smad7 in a time-dependent manner. The human malignant glioma cell lines U87-MG, U373 and GaMG were cultured for 1, 6 and 24 h under hypoxic (0.1% O 2 ) conditions and then they were re-oxygenated. The mRNA expression of NDRG1, HIF-1α SP1, CEBPα, YB-1 and Smad7 was measured using semi-quantitative RT-PCR analysis. Their protein expression was analyzed using western blotting. Our experiments revealed that long-term (24 h), but not short-term hypoxia led to the induction of NDRG1 expression in human glioma cell lines. NDRG1 expression was found to correlate with the protein expression of HIF-1α, SP1, CEBPα, YB-1 and Smad7. The present study suggests for the first time that SP1 regulates NDRG1 expression in glioma cells under hypoxia in a time-dependent manner along with HIF-1α, CEBPα, YB-1 and Smad7. These molecules, each separately or in combination, may possess the potential to become target molecules for antitumor therapeutic approaches particularly in human brain tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Time-and Oxygen-dependent Expression and Regulation Of Ndrg1mentioning

confidence: 99%

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

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“…Targeting this pathway with MEK inhibitors has shown activity in different types of cancers (39,40), including uveal melanoma (13). However, resistance to MEK inhibitors is common and undermines the efficacy of these treatments (41,42).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells

Ambrosini¹,

Khanin

Schwartz

2014

Molecular Cancer Therapeutics

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The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK inhibitor-resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK inhibitor-resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease. Mol Cancer Ther; 13(8); 2073-80. Ó2014 AACR.

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“…Because of having one target, they are a great candidate for therapeutic markers. MEKi don't compete with ATP, they just bind to MEK proteins, and inhibit their association with ERK1/2 [59] . Selumetinib (AZD6244; Astra-Zeneca, Wilmington, DE) is one of the MEKi, and phase II trial results of this inhibitor showed that NSCLC patients treated with Selumetinib and chemotherapy had better progression free survival (PFS, 5.3 and 2.1 months) compared chemotherapy alone.…”

Section: Alterations In Downstream Elements Of Egfr In Nsclc K-ras Mumentioning

confidence: 99%

“…In the third mechanism, other genetic alteration such as PTENinactivating mutations cause constitutive activation of PI3K and LKB1 (liver kinase B1) pathways leading to resistance or reduced sensitivity to MEKi therapy. Because of all these reasons, combinational therapies seem to be more useful in RAS mutated cancers [54,59,61] .…”

Section: Alterations In Downstream Elements Of Egfr In Nsclc K-ras Mumentioning

confidence: 99%

Personalized treatment options in Non-small Cell Lung Cancer

Görgişen¹,

Pehlivanoğlu²,

Ozes³

et al. 2014

Receptor Clin Invest

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Lung cancer is the leading cause of cancer related death among both men and women worldwide [1][2][3] . There are two major groups of lung cancer based on the histological features and response to therapy; non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is also divided to the histological subtypes, and which accounts 80% of lung cancer patients [3,4] . Despite advances in diagnosis, 5-year survival rates are approximately 15% for all cases [5] . Since EGFR (epidermal growth factor receptors) is overexpressed in more than 80% of NSCLC patients, its overexpression is correlated with poor prognosis and chemoresistance. However, only 10% of EGFR1 overexpressing patients respond to EGFR1 TKI (tyrosine kinase inhibitor) therapy implying that EGFR1 overexpression may not be the main factor responsible for NSCLC development [6,7] . Therefore, new therapeutic strategies that specifically target other molecular pathways must be considered as alternative options. In this review, we tried to summarize the most recent studies in treatment of NSLC, and made suggestions on the basis of our results and clinical studies.

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MEK in cancer and cancer therapy

Cited by 208 publications

References 127 publications

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells

Personalized treatment options in Non-small Cell Lung Cancer

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