Oncogenic signaling pathways in ameloblastoma and their implications for precision based therapy

Ameloblastoma is an odontogenic epithelial tumor characterized by a paradoxical clinical behavior. Although histologically benign and typically non-metastatic, it demonstrates aggressive local growth, extensive bone destruction, and a high propensity for recurrence. Surgical resection remains the primary treatment modality but is frequently associated with significant functional and aesthetic morbidity, highlighting the need for alternative, biology-driven therapeutic approaches. Advances in molecular profiling have revealed that ameloblastoma is driven by recurrent, highly specific oncogenic alterations rather than generalized genomic instability. Constitutive activation of the mitogen-activated protein kinase (MAPK) pathway-most commonly through BRAF V600E mutations and particularly prominent in mandibular ameloblastomas-represents the principal oncogenic mechanism in a major molecular subset, with additional involvement of FGFR2 and Hedgehog signaling in distinct subgroups. These pathways, which are key regulators of odontogenic development, confer strong oncogenic pathway dependency while maintaining a developmentally constrained tumor phenotype. Accumulating clinical evidence indicates that pathway-directed therapies, particularly combined BRAF and MEK inhibition, can induce rapid and durable responses in patients with locally advanced, recurrent, or metastatic ameloblastoma. Targeted therapy has also demonstrated potential roles in neoadjuvant tumor downstaging and long-term disease control, enabling surgical de-escalation in selected cases. Emerging strategies targeting FGFR, Hedgehog, epigenetic regulators, and PI3K signaling remain investigational but highlight additional therapeutic vulnerabilities. The objective of this review is to summarize current molecular and clinical evidence supporting pathway-directed targeted therapy in ameloblastoma and to explore its implications for precision-based treatment strategies beyond traditional surgical management.