Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition
Guy Chowers1, Gadi Abebe-Campino2,3, Hana Golan2,3
1Pediatrics B, Edmond and Lili Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel.
Background:
Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.
Methods:
The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay.
Results:
Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib.
Conclusions:
Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies.
Impact:
This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
Insights
Trametinib effectively treated a child with severe Kaposiform lymphangiomatosis (KLA) harboring the NRAS p.Q61R mutation. This MEK inhibitor therapy improved symptoms and demonstrated the potential of targeting the RAS-MAPK pathway in lymphatic anomalies.
Area of Science:
- Oncology
- Genetics
- Vascular Biology
Background:
- Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with limited treatment options.
- Activating NRAS mutations, particularly p.Q61R, are implicated in KLA pathogenesis.
- The RAS-MAPK pathway is a key target for complex lymphatic anomalies.
Purpose of the Study:
- To report the successful use of trametinib in a pediatric patient with severe KLA.
- To investigate the efficacy of targeting the NRAS p.Q61R mutation with a MEK inhibitor.
- To establish an in vitro model for studying KLA and NRAS-driven lymphangiogenesis.
Main Methods:
- NRAS mutation detection in plasma cell-free DNA (cfDNA) using droplet digital PCR.
- In vitro assessment of trametinib efficacy on mutant NRAS lymphatic endothelial cells via 3D spheroid sprouting assay.
- Evaluation of clinical outcomes including thrombocytopenia, pulmonary function, and steroid dependence.
Main Results:
- Trametinib treatment resolved lifelong thrombocytopenia and improved pulmonary function and overall wellbeing.
- In vitro studies confirmed enhanced lymphangiogenic capacity of NRAS p.Q61R cells, with trametinib reversing RAS-MAPK and PI3K-AKT-mTOR pathway overactivation.
- The patient was able to discontinue prolonged systemic steroid treatment.
Conclusions:
- Trametinib offers a promising therapeutic strategy for KLA patients with NRAS pathway mutations.
- Targeting the RAS-MAPK pathway with MEK inhibitors can significantly alter the prognosis of KLA.
- The developed in vitro model provides a platform for further research into KLA pathogenesis and treatment.
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