Molecular-targeted therapy in ameloblastoma: a systematic review

Abstract

Background

Ameloblastoma is a benign odontogenic tumor that predominantly occurs in the mandible and is frequently associated with the BRAF^V600E mutation, which activates the mitogen-activated protein kinase (MAPK) signaling pathway. These mutations indicate potential targets for molecular therapies. This systematic review evaluated the effectiveness of molecular-targeted therapies, particularly BRAF inhibitors such as dabrafenib and vemurafenib, in the treatment of ameloblastoma and their effects on clinical outcomes and quality of life.

Methods

In accordance with PRISMA guidelines (PROSPERO: CRD42024627944), a comprehensive search of databases including PubMed/MEDLINE and Scopus identified 4,620 studies, of which eight case reports met the inclusion criteria for analysis.

Results

The selected case reports involved patients aged 13 to 85, most of whom had experienced prior surgical recurrences. Treatment with BRAF/MEK (mitogen-activated protein kinase kinase) inhibitors resulted in significant tumor regression and improved quality of life, although some manageable side effects were observed.

Conclusion

BRAF inhibitors demonstrate promising efficacy in the management of ameloblastoma, especially in patients harboring BRAF^V600E mutations. These therapies may reduce the necessity for extensive surgical procedures and enhance patient outcomes. Further research is needed to establish standardized treatment protocols and to assess long-term effects on recurrence and quality of life.

INTRODUCTION

Ameloblastoma is a benign odontogenic tumor characterized by a mature fibrous stroma surrounded by odontogenic epithelium, and notably lacks odontogenic ectomesenchyme. This tumor is more frequently found in the mandible than in the maxilla, particularly in the ramus and mandibular angle. Ameloblastoma usually demonstrates slow growth and may remain asymptomatic during its initial stages [1,2]. Although the precise cause of ameloblastoma formation remains unknown, research has identified a significant incidence of this tumor among individuals with BRAF^V600E and SMO^L412F mutations.

The BRAF^V600E mutation activates the mitogen-activated protein kinase (MAPK) pathway. In addition, the expression of ADP-ribosylation factor-like 4c (ARL4C), which is induced by the EGF (epidermal growth factor)-MAPK pathway and Wnt/β-catenin signaling, reflects enhanced epithelial morphogenesis. Excessive ARL4C expression, resulting from alterations in these signaling pathways, contributes to tumor development [3,4]. Previous studies have demonstrated that the RAF1-MEK (mitogen-activated protein kinase kinase)/ERK-ARL4C axis acts in concert with the BRAF^V600E-MEK/ERK pathway to promote the formation of ameloblastoma [5]. Earlier reports indicate that the prevalence of ameloblastoma with the BRAF^V600E mutation reaches 70.49%. This high prevalence highlights the significant role of the BRAF^V600E mutation in the molecular pathogenesis of ameloblastoma. While the precise pathogenic mechanisms of this mutation are still unclear, its elevated incidence suggests the potential for developing new treatments targeting this genetic alteration [6]. The presence of the BRAF^V600E mutation in ameloblastoma is associated with a younger age of onset, with tumors predominantly occurring in the mandible and tending toward later recurrence. In contrast, BRAF wildtype tumors are more often found in the maxilla and typically show earlier recurrence.

The management of ameloblastoma depends on factors such as the extent of involvement, anatomical location, histological type, and tumor size. Currently, various treatment options exist, including radical surgical approaches such as enucleation and segmental resection, which often require reconstructive procedures and may lead to facial disfigurement and functional impairment. Less invasive alternatives, such as marsupialization and decompression, are also considered. Although surgery remains the most effective treatment for ameloblastoma, invasive procedures can result in serious complications, including facial deformities, maxillary bone fractures, tooth loss, and paresthesia [7-9]. In the past decade, novel strategies have emerged that target genetic alterations in ameloblastoma, focusing on the inhibition of signaling pathways implicated in neoplastic progression, particularly the MAPK pathway, with the BRAF^V600E mutation being most prominent [7,10].

Accordingly, the use of BRAF inhibitors before invasive surgery may induce substantial tumor regression, thereby facilitating non-mutilating complete surgical excision, bone regeneration, and organ preservation [4]. Several BRAF inhibitors, including dabrafenib, vemurafenib, and encorafenib, are available for use in molecular-targeted therapy. These agents are employed in the treatment of patients with BRAF-mutant melanoma as well as ameloblastoma. They act by selectively targeting BRAF kinase and interfering with the MAPK signaling pathway, which is critical for regulating the proliferation and survival of melanoma cells [11].

To date, there is a limited number of advanced studies exploring the use of molecular-targeted therapy in ameloblastoma, particularly regarding dabrafenib and vemurafenib. In this review, we summarize reported cases of ameloblastoma treated with molecular-targeted therapies to evaluate their effectiveness, with the goal of improving clinical outcomes for patients with ameloblastoma.

METHODS

The study protocol was registered with PROSPERO under registration number CRD42024627944. This research adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and addresses several key aspects relevant to systematic review methodology. The primary research question examines the effectiveness of moleculartargeted therapy in the treatment of ameloblastoma. Following the PICO framework, the patient population (P) consists of individuals diagnosed with ameloblastoma; the intervention (I) is molecular-targeted therapy; the comparison (C) involves molecular-targeted therapy versus surgical interventions; and the outcomes (O) reflect both clinical responses and subjective complaints related to molecular-targeted therapy in ameloblastoma cases, reported descriptively.

In December 2024, we conducted a comprehensive search of relevant studies in PubMed/MEDLINE, Scopus, SpringerLink, and ScienceDirect. The search terms included: “ameloblastoma,” “BRAF,” “dabrafenib,” “MAPK,” “mutations,” “vemurafenib,” and “^V600E.” The authors did not contact corresponding authors of identified studies for additional data and did not include grey literature in the search. For each included study, we collected the following data: author, publication year, patient age, gender, clinical diagnosis, tumor location and dimensions, treatment administered, and observed outcomes. The eligibility criteria required case reports involving patients with ameloblastoma, regardless of age, sex, tumor location, or size. Studies were included if they reported treatment with molecular-targeted therapies, offered comparative analysis with surgical interventions, or presented outcomes for molecular therapy alone. Only studies published within the last 5 years were considered.

Conversely, the exclusion criteria comprised articles other than case reports, studies not involving molecular-targeted therapy, studies retrieved from outside the specified databases, articles not published in English, and studies for which full texts were unavailable. The search initially yielded 4,620 studies; however, after screening, we identified eight case reports that met the criteria for inclusion in this review, as shown in Fig. 1.

Fig. 1.

Flow diagram of study selection and screening according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

RESULTS

This literature review encompasses eight case reports, reflecting a broad age distribution among the subjects. The youngest patient was 13 years old, and the oldest was 85. The gender distribution was balanced, with an equal ratio of males to females. Several patients experienced recurrence of ameloblastoma following surgical intervention several years prior. In this study, patients diagnosed with ameloblastoma who had BRAF^V600E or MEK gene mutations received treatment with BRAF^V600E or MAPK inhibitors, primarily dabrafenib, vemurafenib, and trametinib.

The effectiveness of molecular-targeted therapy for ameloblastoma can be evaluated through the clinical response to BRAF^V600E inhibitors, given that this mutation is frequently observed in ameloblastoma cases. Conservative treatments such as enucleation are associated with a high recurrence rate. Currently, molecular-based approaches are being implemented to enhance ameloblastoma treatment outcomes by reducing lesion size and improving patients’ quality of life. A summary of the eight selected studies is presented in Table 1. The primary study population included individuals with recurrent ameloblastoma or tumors following previous surgery. All participants had the BRAF^V600E mutation and were recommended for molecularbased therapy. Most patients (62.5%) were treated with a combination of BRAF/MEK inhibitors, specifically dabrafenib and trametinib. Broudic-Guibert et al. [12] reported on a patient who developed recurrent ameloblastoma several years after surgical resection. This patient was treated with vemurafenib, taken twice daily. Although side effects such as arthralgia, nausea, and rash necessitated a dose reduction, treatment was continued, and the final reduced dosage resulted in a 30% decrease in the size of the mandibular tumor as assessed by radiographic imaging. This case highlights the potential of BRAF inhibition as an effective strategy for patients with BRAF-mutated ameloblastoma [12].

Table 1.

Overview of case reports found in the literature

Author (year)	Country	Sex/age	Clinical diagnosis	Tumor site and size	Previous treatment	Treatment	Treatment duration	Side effects	Follow-up duration	Outcome
Broudic-Guibert et al. (2019) [12]	France	F/33	Recurrent metastatic ameloblastoma	Left mandible	Surgical resection	Vemurafenib 960 mg (2 × /day), reduced to 720 mg, and 480 mg PO	15 mo	Mild to moderate arthralgia, nausea, and rash	26 mo	30% decrease in the tumor size
					Chemotherapy
Tan et al. (2016) [16]	USA	M/85	Gnathic ameloblastoma	Mandible, 40 mm in diameter	Enucleation of the tumor with bone grafting	Dabrafenib 150 mg (2 × /day) PO	16 wk	Low energy, plaque-like skin lesions on face, back, and scalp, thickened voice	Not stated	> 90% tumor volume reduction
										Clinically the amounts of viable tumor remained
Kaye et al. (2015) [13]	USA	M/40	Ameloblastoma	Left mandible	Surgical resection	Dabrafenib 150 mg (2 × /day)	8 wk	Not mentioned	Not stated	Reduction of tumor volume in face, oral cavity, and bilateral neck
					Field radiation therapy	Trametinib 2 mg (1 × /day) PO				No subjective complaint
Fernandes et al. (2018) [17]	Brazil	F/29	Recurrent ameloblastoma	Cavernous sinus anterior to the cave of Meckel and exhibiting anterior extension towards the upper orbital fissure (19 × 15 × 16 mm)	Surgical resection, followed by local radiotherapy	Vemurafenib 960 mg (2 × /day) PO	12 mo	Grade mild anorexia	6 mo	Reduction of tumor size and asymptomatic (49.4%)
								Nausea
								Fatigue
Buttner et al. (2023) [1]	Germany	M/36	Recurrent ameloblastoma	Posterior right mandible, extending to the buccal and lingual margins (6.2 × 7.2 × 6.6 cm)	Complete enucleation	Dabrafenib 150 mg	14 mo	No side effects	13 mo	Tumor size reduction (65.7%)
						Trametinib 2 mg PO
Abramson et al. (2022) [14]	USA	M/47	Stage 4 ameloblastoma	Left mandible (size not mentioned)	Surgical resection	Dabrafenib 150 mg (2 × /day)	> 16 mo	Not mentioned	8 yr	Asymptomatic
					Radiation therapy	Trametinib 2 mg (1 × /day) PO				Tumor size reduction
Daws et al. (2021) [18]	USA	F/13	Primary mandibular ameloblastoma	Right mandible (4 × 2.8 × 5.5 cm)	No prior treatment history	Trametinib 1.5 mg (1 × /day) PO	15 wk	Modest pustular facial acne	3 mo	Reduction in tumor size with thin cortical (38.7%)
Raemy et al. (2024) [19]	Switzerland	F/15	Ameloblastoma	Left mandibular angle (25.5 × 18.8 × 24.3 mm)	No prior treatment history	Dabrafenib 75 mg, increased to 150 mg PO	3 mo	Mild effects of fatigue, dry skin, and arthralgia	24 mo	Improvement in cortication with complete ossifica- tion around the alveolar nerve

Kaye et al. [13] described a 40-year-old male patient initially diagnosed with ameloblastoma of the left mandible, who had previously undergone surgical resection and jaw reconstruction. The surgical procedures involved removal of a tumor mass measuring 7.5×5.5 cm, and a partial resection of another mass with diameters of 8.0 cm and 7.0 cm. Genetic mutation testing under Clinical Laboratory Improvement Amendments confirmed the presence of the BRAF^V600E mutation. There was a noticeable reduction in tumor volume in the facial region, oral cavity, and bilateral neck. Subjectively, the patient reported no pain, increased energy, and overall improvement in quality of life. The study demonstrated that both primary and metastatic ameloblastomas with the BRAF^V600E mutation show a significant response to initial treatment using dual BRAF/MEK inhibition [13]. Abramson et al. [14] also demonstrated the effectiveness of administering dabrafenib and trametinib to a 47-year-old male patient who experienced recurrence of ameloblastoma in his left jaw. Treatment with BRAF/MEK inhibitors led to resolution of jaw issues and facial pain within 2 weeks, along with a reduction in tumor size. Meanwhile, several patients received molecular-based treatment with BRAF inhibitors alone [14].

This aligns with research conducted by Buttner et al. [1], in which a 36-year-old male patient exhibited a reduction in the size of a tumor lesion in the posterior mandible after receiving dabrafenib (150 mg) and trametinib (2 mg daily) for 18 months. Magnetic resonance imaging revealed a decrease in tumor size from 72.6 mm to 55.9 mm. Remarkably, no recurrence was observed over 1 year. In another case, a 26-year-old female patient with recurrent metastatic ameloblastoma, which developed 13 years after initial surgical resection with clear margins, was treated with the same doses of dabrafenib and trametinib. After 12 weeks, a computed tomography scan showed a positive response, and treatment continued for a total of 30 weeks [15].

Tan et al. [16] reported that treatment with dabrafenib also yielded positive results in an 85-year-old patient who had previously undergone tumor enucleation and bone grafting. Four months later, tumor regrowth in the mandible was observed, measuring 4.5 cm. Following genetic mutation analysis, dabrafenib was administered. Side effects included actinic keratosis and low energy. After 16 weeks of treatment, there was more than a 90% reduction in tumor volume. Clinically, some viable tumor tissue remained, which could potentially be addressed with dual-targeted therapy and prolonged treatment duration [16]. In another case, a patient presented with symptoms related to the right cavernous sinus, specifically anterior to Meckel’s cave, extending toward the upper orbital fissure. Following mutation analysis, vemurafenib was administered for 2 weeks, resulting in a substantial decrease in lesion size (from 24×18×15 mm to 18×13×14 mm). The patient reported no pain and tolerated the medication well [17]. Daws et al. [18] treated a patient with swelling in the right mandible using trametinib, a MAPK pathway inhibitor, for 1 year. Significant reduction in lesion size was observed after just 2 weeks of molecular treatment.

Lastly, Raemy et al. [19] described a case of ameloblastoma in which histopathological examination revealed a BRAF^V600E mutation. The diagnosis was confirmed through histopathological analysis, and treatment was initiated with dabrafenib at a dose of 75 mg, increased to 150 mg after 2 weeks. The goal of dabrafenib therapy was to reduce tumor size, minimizing the need for extensive surgery and enabling simple enucleation without injury to the inferior alveolar nerve or the second molar. After 2 months of dabrafenib therapy, cone-beam computed tomography showed a favorable response with evidence of progressive mineralization. By the 3rd month, there was increased cortication and complete ossification around the alveolar nerve. The patient subsequently underwent surgery. Biopsy of the newly formed bone showed no evidence of BRAF mutation or alterations and demonstrated good histological quality. Serial followup and postoperative cone-beam computed tomography confirmed appropriate healing of the operative site with no recurrence [19]. These findings collectively support the efficacy of molecular-targeted therapy in reducing tumor burden, facilitating less invasive surgical approaches, and preserving anatomical structures in the management of ameloblastoma. This case series further underscores the potential role of BRAF inhibitors as an effective neoadjuvant therapy in select ameloblastoma patients.

DISCUSSION

Ameloblastoma is classified as a benign tumor arising from odontogenic tissue, and is frequently associated with the BRAF^V600E mutation. The high incidence of these mutations highlights the potential for molecular therapies in the treatment of ameloblastoma. One promising strategy is the use of BRAF inhibitors as neoadjuvant therapy before surgical intervention. Research indicates that approximately 82% of ameloblastoma cases exhibit the BRAF^V600E mutation, with a higher frequency in mandibular tumors and among younger individuals. Notably, some studies have observed that patients harboring the BRAF^V600E mutation have a lower risk of tumor recurrence compared to those with multiple gene mutations. In the studies reviewed, all patients demonstrated a reduction in tumor size following treatment with BRAF/MEK inhibitors. While some experienced side effects such as nausea, arthralgia, and rash, combination therapy with BRAF and MEK inhibitors has been shown to improve response rates and is associated with manageable toxicity profiles [1].

Recent research, including the study by Fujii et al. in 2022 [4], has shown that BRAF^V600E-driven ameloblastoma upregulates ARL4C expression, a downstream effector of both the MAPK and Wnt/β-catenin pathways, which promotes osteoclast formation and bone resorption. By inhibiting the MAPK pathway at multiple points (BRAF and MEK), drugs such as dabrafenib and trametinib can disrupt this pathological signaling cascade, thereby halting both tumor proliferation and bone destruction [4]. A notable difference in treatment outcomes was observed between patients with a history of prior surgical intervention and those who had not undergone surgery before moleculartargeted therapy. Patients with previous surgeries—particularly those with recurrences many years after initial radical resections— often presented with larger or more complex lesions. In these cases, BRAF/MEK inhibitors were most commonly used as salvage therapy to control recurrent or metastatic disease. Despite their surgical history, many of these patients experienced substantial tumor regression, symptom relief, and improved quality of life with targeted therapy. Conversely, patients who received molecular therapy as a first-line intervention— without prior surgery—also responded favorably, with early imaging often revealing significant tumor shrinkage, which in turn allowed for more conservative surgeries such as enucleation rather than radical resection [4].

These findings suggest that although molecular-targeted therapy is effective in both previously treated and untreated patients, its role may be especially impactful when used upfront to reduce tumor burden and avoid mutilating surgeries. This is particularly relevant for younger patients or those with anatomically challenging tumors. Thus, the timing of targeted therapy can influence both therapeutic outcomes and the extent of subsequent surgical morbidity. Most patients were treated with dabrafenib at a dose of 150 mg together with trametinib at 2 mg. Clinical responses to BRAF/MEK inhibitors were generally positive, as evidenced by tumor shrinkage, although residual viable tumor tissue was sometimes detected [16]. This observation is consistent with reports that BRAF-mutated ameloblastoma is more common in younger individuals. Both imaging and histopathological evaluation confirmed tumor reduction, although the BRAF mutation remained present. The use of molecular-targeted therapies in ameloblastoma—specifically dabrafenib, trametinib, and vemurafenib—has been linked to a range of adverse effects. Overall, these drugs are generally well tolerated, but clinicians should closely monitor for side effects. Across the reviewed cases, the most commonly reported adverse events were fever and myalgia, arthralgia, nausea, skin lesions or rash, anorexia, and fatigue. Most side effects were grade 1–2 in severity and could be managed with dose reduction, temporary treatment interruption, or supportive care [20]. These findings underscore the need for vigilant monitoring, particularly for dermatological, hepatic, and systemic symptoms. In addition, careful dose titration and proactive management strategies are essential for maintaining treatment tolerability without compromising efficacy [20].

The use of BRAF inhibitors may reduce the need for extensive surgical procedures, permitting more localized and less invasive surgeries, and thereby minimizing surgical resections. The treatment outcomes associated with molecular-targeted therapy— especially BRAF and MEK inhibitors—have been promising for ameloblastoma, particularly in cases with the BRAF^V600E mutation. In the reviewed studies, most patients experienced substantial tumor reduction, which was frequently accompanied by symptomatic improvement, including relief of pain and swelling, increased energy levels, and enhanced overall quality of life. These consistent findings indicate that BRAF/MEK inhibitors not only decrease tumor burden but also contribute to improved functional outcomes and a reduced need for mutilating surgery, especially in younger or recurrent cases. However, it is important to note that complete pathological remission is rarely achieved; viable tumor cells may persist despite marked regression on imaging, underscoring the importance of combining targeted therapy with definitive surgical excision to achieve curative outcomes [12,16,17].

The efficacy of molecular-targeted therapy, particularly BRAF and MEK inhibitors such as dabrafenib, trametinib, and vemurafenib, has been consistently demonstrated across the reviewed case reports. In patients with BRAF^V600E-mutated ameloblastoma, these agents have provided substantial clinical benefits, including significant tumor volume reduction, delay or avoidance of radical surgery, and improved symptom control. These findings are consistent with molecular studies showing that the BRAF^V600E mutation leads to constitutive activation of the MAPK pathway, thereby promoting tumorigenesis. Accordingly, targeted inhibition of this pathway represents a rational and effective therapeutic strategy for ameloblastoma patients harboring this mutation. While some tumors exhibit only partial responses with residual viable tissue, the majority of cases show significant radiological and symptomatic improvement, suggesting that molecular-targeted therapy may serve as a neoadjuvant modality prior to conservative surgical approaches [6,12,17].

Neoadjuvant therapy has proven effective in lowering local recurrence rates. Across the eight case reports analyzed in this systematic review, the use of targeted therapy resulted in substantial tumor volume reduction, with many patients experiencing improved quality of life, pain relief, and preservation of function. For example, dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) consistently led to tumor size reduction, as evidenced in reports by Buttner et al. [1] and Abramson et al. [14]. In some cases, this tumor shrinkage enabled less invasive surgical procedures, such as enucleation rather than radical resection, thus reducing the risks of facial disfigurement and nerve injury. Although most patients responded positively, residual viable tumor tissue was sometimes observed after therapy, indicating that targeted therapy alone is not curative. Therefore, it is best considered as a neoadjuvant option—used to reduce tumor burden before surgery or in cases where surgery is not feasible [1,4,14].

BRAF inhibitors have also demonstrated beneficial effects on surrounding soft tissues. In several cases, patients exhibited improvements in facial symmetry, soft tissue swelling, and pain, indicating that tumor volume reduction can also alleviate soft tissue pressure and inflammation. For example, Kaye et al. [13] reported a notable reduction in soft tissue mass across the facial, oral, and cervical regions following BRAF/MEK inhibitor therapy, with patients reporting increased energy and reduced facial discomfort. This highlights the role of targeted therapy not only in managing bone-invasive ameloblastoma but also in improving soft tissue burden and quality-of-life outcomes. Furthermore, in patients with a history of previous surgical resections— particularly those with recurrence—BRAF/MEK inhibitors have served as effective adjuvant therapies, delaying or avoiding the need for repeat extensive surgery. These agents helped control residual or unresectable tissue by stabilizing or reducing soft tissue tumor extensions. These findings suggest that even in post-surgical settings, targeted therapy provides dual benefits: mitigating tumor burden in both hard and soft tissues and improving functional and aesthetic outcomes. Incorporating BRAF inhibitors in the postoperative or recurrent setting may therefore support long-term disease control while minimizing surgical morbidity [13,14,19]. While the long-term efficacy and recurrence rates following targeted therapy are still under investigation, the use of BRAF and MEK inhibitors represents a significant advancement in ameloblastoma management, offering patients less invasive options with favorable outcomes. In conclusion, definitive surgical treatment remains necessary for ameloblastoma cases, typically requiring radical resection with a safety margin of 1–1.5 cm. This indicates that although molecular-targeted therapies such as BRAF/MEK inhibitors are effective, they do not constitute a definitive cure [6,10,13,17].

CONCLUSION

A deeper understanding of the molecular pathology associated with ameloblastoma can lead to improved treatment strategies. The implementation of BRAF/MEK inhibitors may decrease postoperative complications by reducing the extent of surgical intervention required for tumor lesions. Moreover, in patients with recurrent disease after prior surgical interventions, BRAF/MEK inhibitors may serve as effective adjuvant therapies, helping to delay or even avoid further mutilating procedures. Overall, patients’ quality of life appears to be better compared to those who undergo radical resection alone. Based on the studies reviewed, it is advisable to consider administering BRAF/MEK inhibitors before surgical procedures, particularly in younger patients.

Abbreviations

ARL4C

ADP-ribosylation factor-like 4c

EGF

epidermal growth factor

MAPK

mitogen-activated protein kinase

MEK

mitogen-activated protein kinase kinase

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses