Trametinib for multiple non-ossifying fibromas due to KRAS mosaic mutations: two case reports

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. 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. 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. Hence, trametinib constitutes a promising precision therapeutic approach for severe KRAS-related NOFs. Non-ossifying fibromas (NOFs) are common non-cancerous bone lesions in children, but when they affect multiple bones, they weaken the skeleton and cause repeated fractures. No specific treatment currently exists. We studied two children who had multiple NOFs caused by changes in a gene (part of their DNA) called KRAS. To understand the consequences of these changes, we tested them in a cell model in the laboratory and used a drug called trametinib, which blocks an overactive KRAS pathway. The treatment reduced abnormal activity of the KRAS pathway in the cell model and, in the two patients, resulted in bone lesions healing and no further fracture. These findings suggest that trametinib is a promising targeted therapy for children with severe KRAS-related bone fragility. Vincent et al. report the effect of MEK inhibitor trametinib in two children with syndromic KRAS-related multiple non-ossifying fibromas (NOFs). This treatment in vitro reduces KRAS pathway hyperactivation and in vivo induces reossification of NOFs, thus representing a promising targeted therapy for severe KRAS-related bone fragility.