Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.1 (
protein kinase
)
81,284
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Major advances have been made in understanding the pathogenesis of
Erdheim-Chester disease
(
ECD
) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management, emphasizing the importance of the activated mitogen-associated
protein kinase
pathway in this disease. However, incomplete responsiveness, potentially limiting adverse effects, and the occurrence of treatment resistance to BRAF inhibition observed in other
BRAF
-mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with
ECD
who carried the
BRAF
V600E
mutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing
ECD
lesion revealed a somatic
KRAS
Q61H
mutation without the presence of
BRAF
V600E
Accordingly, the addition of MEK-inhibiting trametinib to BRAF-inhibiting dabrafenib was able to overcome acquired partial treatment resistance. This is the first report of treatment resistance as a result of a secondary MAPK pathway-activating mutation during BRAF inhibition in
ECD
. This case contributes to the ongoing efforts of simultaneous BRAF/MEK inhibition as a promising strategy in
ECD
.
...
PMID:Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both
BRAF
and
KRAS
mutations. 2794 Apr 76
The revised 2016 World Health Organization classification introduced
Erdheim-Chester disease
(
ECD
) as a provisional entity within the histiocytic and dendritic cell neoplasms separate from the juvenile xanthogranuloma family based on distinct molecular features. However, evolving knowledge regarding the molecular and genetic aberrations in addition to common clinical features of
ECD
support the classification of
ECD
together with Langerhans cell histiocytosis (LCH). Accordingly,
ECD
can be thought of as an inflammatory myeloid clonal disorder based on the detection of various activating mutations along the mitogen activated
protein kinase
-extracellular signal regulated kinase (MAPK-ERK) pathway with most notable variant being a valine to a glutamic acid substitution at amino acid 600 in the B-rapidly accelerated fibrosarcoma protein (BRAFV600E). In this group, targeted therapy with a B-Raf inhibitor alone or combined with a MAPK-ERK (MEK) inhibitor has shown promising results based on several case reports. Currently, two phase II trials with BRAF inhibitors are underway and could potentially change the standard of care. MEK inhibitors may also be efficacious in
ECD
harboring mutations in MAP2K1; other potential targetable aberrations include programed cell death receptor 1 and mutations in phosphoinositide 3-kinase.
...
PMID:Erdheim-Chester Disease: Comprehensive Review of Molecular Profiling and Therapeutic Advances. 2855 13
