What are MEK mutations?
What are MEK mutations?
MAPK/ERK kinase (MEK) 1/2 are central signaling proteins that serve as specificity determinants of the MAPK/ERK cascade. More than twenty activating mutations have been reported for MEK1/2, and many of them are known to cause diseases such as cancers, arteriovenous malformation and RASopathies.
What drugs are MEK inhibitors?
To date, four MEK inhibitors have been approved by the United States Food and Drug Administration (FDA), including trametinib, binimetinib, selumetinib, and cobimetinib [19–22].
What does MEK stand for in MEK inhibitor?
The current development status of mitogen-activated protein kinase kinase (MEK) inhibitors, including the preclinical data and clinical study progress, has been summarized in this review.
Is MEK inhibitor ImmunoTherapy?
The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment | Journal for ImmunoTherapy of Cancer.
How does the BRAF gene become mutated?
A BRAF mutation can be inherited from your parents or acquired later in life. Mutations that happen later in life are usually caused by the environment or from a mistake that happens in your body during cell division. Inherited BRAF mutations are very rare, but they can cause serious health problems.
How do arylamine inhibitors cause resistance to MEK1?
Binding of arylamine inhibitors within this pocket prevents the structural reorganization of α-helix C and other motifs, which generates a catalytically active MEK1 conformation. Thus, primary mutations may cause resistance either by direct interference or through altered C helix conformation.
What is the pathophysiology of MEK1 p124l?
One such mutation, MEK1 (P124L), was identified in a resistant metastatic focus that emerged in a melanoma patient treated with AZD6244. Both MEK1 (P124L) and MEK1 (Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor.
Is MEK1 cross-resistant to AZD6244 and PLX4720?
Both MEK1 (P124L) and MEK1 (Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor. However, exposing BRAF -mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones.
Is MEK dependency relevant in melanoma?
We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro, as well as tumors obtained from relapsed patients following treatment with AZD6244, an allosteric MEK inhibitor.
