Case report: Successful use of MEK inhibitors as an adjuvant approach in the treatment of pediatric MAP4-RAF1 fusion-positive solid tumor

Introduction

The MAPK signaling pathway is one of the most common pathways in cancer mutations. Studies demonstrate that ERK signal transduction relies on RAS-induced RAF dimerization, tightly regulated by feedback mechanisms¹. Activated RAS binds to members of the RAF family, promoting both homodimerization and heterodimerization, leading to their activation². This subsequently initiates the MEK/ERK kinase cascade, resulting in ERK phosphorylation of downstream effectors in the pathway. RAF proteins, which include ARAF, BRAF, and RAF1 (c-RAF), play a critical role in cellular signaling. BRAF gene mutations are present in approximately 7%–10% of cancers, whereas mutations in ARAF and RAF1 are relatively rare. These kinases function downstream of RAS as integral components of the MAPK (RAF/MEK/ERK) signaling cascade. Gene fusions involving BRAF or RAF1 can activate the MAPK pathway, potentially acting as oncogenic drivers and representing promising targets for therapeutic intervention in various cancer types.

RAF1 gene fusion presents a unique mechanism of RAF activation and has been identified in various solid tumor types4. However, there have been limited reports on the use of RAF or MEK inhibitors to treat tumors harboring RAF1 fusion. Therefore, the sensitivity of RAF1 fusions to drugs remains unclear and contentious. In this study, we report a case of a pediatric solid tumor positive for MAP4-RAF1^{exon15:exon10} fusion, successfully treated with MEK inhibitors as an adjunctive therapy. Structural analysis suggests potential disruption of the self-inhibitory state (S²⁵⁸, S⁶²¹) of the 14-3-3 dimer by the MAP4-RAF1 fusion protein. Drug predictions and simulations indicate trametinib may be more effective, while sorafenib may exhibit lower efficacy. This study contributes to a better understanding of this rare and challenging clinical scenario.

Results

Patient information and clinical findings

The patient, an 8-year-old boy, presented with lower extremity pain for one month. No family history of congenital malformations or tumors was reported.

Pelvic ultrasonography and enhanced CT examination revealed left pelvic mass invading the left sacral canal (Fig. 1). Tumor marker examination showed that serum neuron-specific enolase (NSE), alpha fetoprotein (AFP), urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) were all normal. Open biopsy pathology of the tumor indicated vascular rich malignant spindle cell neoplasm with IHC positive for SMA and S100 (Fig. 1 A), and the NGS result showed