Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0268596 (EMA)
 2,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The death domain of the type 1 tumor necrosis factor receptor (TNFR1) mediates interactions with several proteins involved in signaling the downstream effects of TNF. We have used the yeast interaction trap to isolate a protein, MADD, that associates with the death domain of TNFR1 through its own C-terminal death domain. MADD interacts with TNFR1 residues that are critical for signal generation and coimmunoprecipitates with TNFR1, implicating MADD as a component of the TNFR1 signaling complex. Importantly, we have found that overexpression of MADD activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK), and expression of the MADD death domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A2. These data indicate that MADD links TNFR1 with MAP kinase activation and arachidonic acid release and provide further insight into the mechanisms by which TNF exerts its pleiotropic effects.
 ...
PMID:MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase. 911 75

Molecular characterization of non-small cell lung cancer (NSCLC) marked an historical turning point for the treatment of lung tumors harboring kinase alterations suitable for specific targeted drugs inhibition, translating into major clinical improvements. Besides EGFR, ALK and ROS1, BRAF represents a novel therapeutic target for the treatment of advanced NSCLC. BRAF mutations, found in 1.5-3.5% of NSCLC, are responsible of the constitutive activation of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Clinical trials evaluating the efficacy of the BRAF inhibitor dabrafenib in combination with the downstream MEK inhibitor trametinib in metastatic BRAFV600E-mutated NSCLC guaranteed FDA and EMA rapid approval of the combination regimen in this clinical setting. In line with the striking results observed in metastatic melanoma harboring the same molecular alteration, BRAF and MEK inhibition should be considered a new standard of care in this molecular subtype of NSCLC. In the present review, we propose an overview of the available evidence about BRAF in NSCLC mutations (V600E and non-V600E), from biological significance to emerging clinical implications of BRAF mutations detection. Focusing on the current strategies to act against the mutated kinase, we moreover approach additional strategies to overcome treatment resistance.
 ...
PMID:BRAF in non-small cell lung cancer (NSCLC): Pickaxing another brick in the wall. 2972 95