Targeting mitogen‐activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems†

Hennig, Matthew; Yip-Schneider, Michele; Wentz, Sabrina; Wu, Hsin-Jung; Hekmatyar, S. K.; Klein, Patrick; Bansal, Navin; Schmidt, C. Max

doi:10.1002/hep.23470

Cited by 27 publications

(20 citation statements)

References 32 publications

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“…At the level of hepatocellular carcinoma cell lines, MEK inhibitors displayed a high, dose-dependent efficacy in inhibition of pERK1/2 phosphorylation compared with sorafenib, which is in concordance to other reports (17,32). MEK inhibitors did not block the phosphorylation site of MEK, which resulted in an accumulation of p-MEK1 as demonstrated in previous studies (17,32).…”

Section: Discussionsupporting

confidence: 90%

“…MEK inhibitors did not block the phosphorylation site of MEK, which resulted in an accumulation of p-MEK1 as demonstrated in previous studies (17,32). Most importantly, treatment of HepG2 and Hep3B cells with low-dose sorafenib resulted in increased MEK1 and ERK1/2 phosphorylation, whereas inhibition of the MAPK pathway was only achieved at concentrations higher than 5 mmol/L.…”

Section: Discussionmentioning

confidence: 49%

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BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

Breunig

Mueller

Umansky

et al. 2014

Clinical Cancer Research

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Purpose: Small molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, such as sorafenib, represent novel treatment options for advanced hepatocellular carcinoma. The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors.Experimental Design: Hepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis, and chemokine secretion.Results: Hepatocellular carcinoma cell lines responded differentially to these inhibitors in a dosedependent manner, even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis, and chemokine secretion. Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells.Conclusions: Oncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors. Clin Cancer Res; 20(9); 2410-23. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 49%

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

Breunig

Mueller

Umansky

et al. 2014

Clinical Cancer Research

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“…In order to verify whether these clinically relevant inhibitors pass the blood-brain barrier, we tested the MEK1/2 inhibitors PD325901, Trametinib (GSK1102212) and Selumetinib (AZD6244), and the Raf inhibitor Dabrafenib (GSK2118436). The doses of the inhibitors, as indicated below, were selected on the basis of their previously reported effects on tumour formation (Hennig et al, 2010; Gilmartin et al, 2011; Hofmann et al, 2012; King et al, 2013). For all compounds we followed the same procedure: the inhibitor was given (i.p.)…”

Section: Resultsmentioning

confidence: 99%

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Papale

Morella

Indrigo

et al. 2016

eLife

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Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.DOI: http://dx.doi.org/10.7554/eLife.17111.001

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“…38 We confirmed this finding with a much more potent and highly sensitive inhibitor of MEK kinase, PD0325901. 46 Even at the highest concentration used in our study, only partial reversal (42%) of TGF-β1-mediated suppression of apoptosis was observed, indicating that additional pathways are responsible for TGF-β1-mediated protection.…”

Section: A B Cmentioning

confidence: 50%

TGF-β1 Increases Resistance of NIH/3T3 Fibroblasts Toward Apoptosis Through Activation of Smad2/3 and Erk1/2 Pathways

Negmadjanov¹,

Holmuhamedov²,

Emelyanova³

et al. 2016

Journal of Patient-Centered Research and Reviews

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Journal of Patient-Centered Research and Reviews ( JPCRR) is a peerreviewed scientific journal whose mission is to communicate clinical and bench research findings, with the goal of improving the quality of human health, the care of the individual patient, and the care of populations. Recommended CitationNegmadjanov U, Holmuhamedov A, Emelyanova L, Xu H, Rizvi F, Ross GR, Tajik AJ, Shi Y, Holmuhamedov E, Jahangir A. TGF-β1 increases resistance of NIH/3T3 fibroblasts toward apoptosis through activation of Smad2/3 and Erk1/2 pathways. J Patient Cent Res Rev. 2016;3:187-98.

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Targeting mitogen‐activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems†

Cited by 27 publications

References 32 publications

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

TGF-β1 Increases Resistance of NIH/3T3 Fibroblasts Toward Apoptosis Through Activation of Smad2/3 and Erk1/2 Pathways

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