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Trametinib for multiple non-ossifying fibromas due to KRAS mosaic mutations: two case reports
Marie Vincent1,2, Soizic Tiriau3, Marine Fouillet-Desjonqueres4,5
1Service de Génétique Médicale, CHU Nantes, Nantes, France. marie.vincent@chu-nantes.fr.
Background:
KRAS mosaic activating variants are the main cause of non-ossifying fibromas (NOFs), the most common benign lesion of the growing skeleton. Multifocal NOFs cause bone fragility, and no specific treatment is currently available.
Methods:
We report two children, carrying mosaic KRAS variants (p.G13D and p.A146T), presenting with oculoectodermal syndrome and recurrent fractures due to progressive polyostotic NOFs. To assess the impact of these mutations on KRAS function, we conducted transient KRAS overexpression in HEK293 cells and then tested the effect of the MEK-inhibitor trametinib at the cellular level.
Results:
We show that trametinib yields, in vitro, significant reduction of RAS-pathway hyperactivation induced by the two KRAS variants and, in vivo, remarkable clinical and radiological improvement with no recurrence of fractures and reossification of NOFs under treatment; resurgence of lesions is observed one year after stopping treatment.
Conclusions:
Hence, trametinib constitutes a promising precision therapeutic approach for severe KRAS-related NOFs.
Insights
Trametinib effectively treats severe non-ossifying fibromas (NOFs) caused by KRAS variants. This MEK inhibitor reduced lesions and fractures in patients, showing promise for precision therapy.
Area of Science:
- Oncology
- Genetics
- Pediatrics
Background:
- Mosaic KRAS variants cause non-ossifying fibromas (NOFs), the most common benign bone lesions in children.
- Multifocal NOFs lead to bone fragility, with no current targeted treatments.
Purpose of the Study:
- To investigate the efficacy of trametinib in treating severe, progressive polyostotic NOFs.
- To assess the impact of mosaic KRAS variants on RAS-pathway signaling and response to MEK inhibition.
Main Methods:
- Two children with mosaic KRAS variants (p.G13D, p.A146T) and oculoectodermal syndrome were treated with trametinib.
- In vitro studies involved KRAS overexpression in HEK293 cells to assess pathway hyperactivation.
- In vivo assessment included clinical and radiological monitoring of NOF progression and fractures during treatment.
Main Results:
- Trametinib significantly reduced RAS-pathway hyperactivation in vitro.
- Patients showed remarkable clinical and radiological improvement, including fracture reduction and NOF reossification.
- Lesion resurgence occurred one year after treatment cessation, indicating the need for sustained therapy.
Conclusions:
- Trametinib is a promising precision therapeutic agent for severe KRAS-related NOFs.
- Targeting the RAS pathway with MEK inhibitors offers a viable treatment strategy for these challenging bone lesions.
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