ISSN: 2822-0838 Online

Gene Mutations in the FGF-MAPK Signaling Pathway and Targeted Therapy in Ameloblastoma

Nattanit Boonsong, Kittipong Laosuwan, Nakarin Kitkumthorn, Puangwan Lapthanasupkul, Wacharaporn Thosaporn, and Anak Iamaroon*
Published Date : 2022-10-18
Journal Issues : Number 4, October-December 2022

Abstract Ameloblastoma is one of the most common odontogenic tumors in AsiaIn the past decade, many studies have shown gene mutations in the mitogen-activated protein kinase (MAPKsignaling pathway, especially on an extracellular signal-regulated kinase 1/(ERK1/2signaling pathwayMutations of fibroblast growth factor receptor 2 (FGFR2), rat sarcoma virus (RAS)and B-rapidly accelerated fibrosarcoma (BRAFare able to cause a continuous activation of the ERK1/2 signaling pathway, hence uncontrolled tumor cell proliferationDue to the ERK1/2 signaling pathway role in cell growth and cell survival, upregulation of this pathway can cause approximately one-third of human tumors including ameloblastomaAfter the discovery of gene mutations in several cancers, many inhibitors have been designed to target these mutationsWe, here, reviewed the alteration of the FGF-MAPK signaling pathway in ameloblastoma and targeted treatment used as an adjuvant or neoadjuvant therapy for ameloblastoma especially in cases where wide surgical resection is needed.


KeywordsGenetic, Growth factor, Mutation, Targeted therapy 


FundingResearch Funding for graduate students from Faculty of Dentistry and Chiang Mai University Presidential Scholarship, Chiang Mai University, Thailand.


Citation: Boonsong, N., Laosuwan, K., Kitkumthorn, N., Lapthanasupkul, P., Thosaporn, W., Iamaroon, A., 2022Gene mutations in the FGF-MAPK signaling pathway and targeted therapy in ameloblastomaCMUJNatSci21(4): e2022054.



Ameloblastoma is a benign, slow-growing, and locally invasive odontogenic tumor. It is one of the most common odontogenic tumors in Asia (Dhanuthai et al., 2012; Saghravanian et al., 2016). Although the etiology of ameloblastoma is unclear, previous studies have implicated that dysregulation of cell cycle, apoptosis, tumor suppressor proteins, osteoclastic mechanism, matrix metalloproteinase activity, and certain signaling pathways involve in the pathogenesis of ameloblastoma (You et al., 2019). Recent studies have shown gene mutations particularly of B-rapidly accelerated fibrosarcoma (BRAF) in the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, a part of the mitogen-activated protein kinase (MAPK) signaling pathway, may play a role in the etiology of ameloblastoma. Once BRAF is mutated, a continuous activation of the ERK1/2 signaling pathway follows, leading to autonomous cell proliferation (Guo et al., 2020). Approximately one-third of human tumors including ameloblastoma are caused by mutations in the ERK1/2 signaling pathway (Uehling and Harris, 2015). Moreover, the ERK1/2 signaling pathway may play an important role in tumor invasion, angiogenesis, and metastasis (Guo et al., 2020). After the discovery of gene mutations in several cancers, many inhibitors have been designed to target these mutations (Uehling and Harris, 2015). A few case reports of using RAF and mitogen-activated protein kinase kinase (MEK) inhibitors in ameloblastoma have shown a reduction in tumor sizes. Collectively, these inhibitors are suggested as an adjuvant or neoadjuvant targeted therapy in ameloblastoma to help in improving functions and esthetics in patients with ameloblastoma (Fernandes et al., 2018; Kaye et al., 2015).



Ameloblastoma is a benign, slow-growing, and locally invasive odontogenic tumor. Ameloblastoma is one of the most common odontogenic tumors, believed to arise from rests of the dental lamina, a developing enamel organ, the epithelial lining of an odontogenic cyst, or the basal cells of the oral mucosa (Neville BW et al., 2016; Saghravanian et al., 2016; Konchanthes and Chamusi, 2018). According to The World Health Organization (WHO) Classification of Odontogenic Tumors in 2017, apart from the conventional ameloblastoma, there are other variants, including unicystic ameloblastoma, extraosseous/peripheral ameloblastoma, and metastasizing ameloblastoma (El-Naggar et al., 2017).


Ameloblastoma, also known as multicystic/solid ameloblastoma, occurs in a wide range of ages but is more common in the third to the fifth decades of life with no significant gender predilection. Approximately 10–15% of ameloblastoma occurs in the younger population (Effiom et al., 2018). The mandible, especially in posterior part, is the most common location involved. The radiographic feature of ameloblastoma can be either unilocular or multilocular radiolucency (Neville BW  et al., 2016). Due to the high recurrence rate of ameloblastoma, the recommended treatment for ameloblastoma is surgery with wide resection. For a wide resection, a margin of 1.5-2 cm beyond the radiological limit of the lesion is recommended. Even after the resection with adequacy, the recurrence rate remains 13-15% (El-Naggar et al., 2017; Neville BW et al., 2016). The quality of life of patients with ameloblastoma after surgical treatment may be poor due to facial deformity and limitation of masticatory functions. These may also affect the psychological status of the patients (Effiom et al., 2018).


Recent studies have shown that gene mutations in the FGF-MAPK signaling pathway may play a significant role in the pathogenesis of ameloblastoma (El-Naggar et al., 2017). Some inhibitors of the FGF-MAPK signaling pathway are currently used as targeted therapies for ameloblastoma.  Moreover, novel inhibitors are being explored, aiming to help in the reduction of surgical treatment for patients with ameloblastoma (Uehling and Harris, 2015; Chae et al., 2017; Kommalapati et al., 2021).


The FGF-MAPK signaling pathway with tumorigenesis

The MAPK signaling pathway comprises a signaling pathway that operates through sequential phosphorylation events. This pathway has a crucial role in responding to various extracellular factors such as mitogens, hormones, and stresses and regulating many cellular processes such as cell proliferation and differentiation. In the MAPK signaling pathway, the transmission of signals is initiated by the activation of a small G protein, RAS. Subsequently, the signals are transmitted downstream by three to five tiers of specific cytosolic protein kinases, including RAF, MEK, and ERK. The kinases in each tier are phosphorylated and then activate the kinases located in their downstream signaling proteins (Keshet and Seger, 2010).


The MAPK pathway has four minor pathways, namely ERK1/2, c-Jun N-terminal kinase 1–3 (JNK1–3), p38 MAPK ⍺, β, ɣ,


Gene mutations in the FGF-MAPK signaling pathway in ameloblastoma.


Table 1Previous studies on gene mutations in the FGF-MAPK signaling pathway in Ameloblastoma.


                      Gene mutations in MAPK signaling pathway in ameloblastoma




Sample size (n)

Mutation site

Frequency (%)



Brown et al., 2014


C382R and V395D


Mandible (33.3%)

Maxilla (66.7%)


Sweeney et al., 2014


C382R and N549K


Mandible (40.0%)

Maxilla (40.0%)

Other (20.0%


Sweeney et al., 2014



14.0 (KRAS)

Maxilla (100.0%)


Brown et al., 2014


G12S, Q61R,

and Q61K

20.0 (8.0% of KRAS,
6.0% of NRAS and
6.0% of HRAS)

Mandible (30.0%)

Maxilla (70.0%)



Sweeney et al., 2014







Mandible (69.3%)

Maxilla (23.0%)

Other (7.7%)


Brown et al., 2014



Mandible (94.4%)

Maxilla (5.6%)



Bartels et al., 2018



Not available



Kelppe et al., 2019




Mandible (100.0%)



do Canto et al., 2019



Mandible (100.0%)



Oh et al., 2019



Mandible (92.6%)

Maxilla (7.4%)




Lapthanasupkul et al., 2020



Mandible (97.3%)

Maxilla (2.7%)




Seki-Soda et al., 2020



Mandible (100.0%)



Derakhshan et al., 2020



Mandible (78.3%)

Maxilla (21.7%)




Gene mutations in FGF-MAPK signaling proteins, including FGFR, RAS, RAF, MEK, and ERK lead to tumorigenesis of many human cancers aforementioned (Burotto et al., 2014; Brown and Betz, 2015; Guo et al., 2020). BRAFV600E, in particular, is the most frequent gene mutation in ameloblastoma (Gültekin et al., 2018).


Recent studies have shown that mutation of BRAF at BRAFV600E position, resulting in replacement of valine to glutamic acid at codon 600, is mainly involved in ameloblastoma. Mutation of BRAFV600E can also be found in other human neoplasms, including melanoma, thyroid, ovarian, colorectal, and lung cancers (Davies et al., 2002; Dhillon et al., 2007; Ranjbari et al., 2013). A recent study in Thai patients showed that BRAFV600E mutation occurred in 72.5% with no specific association with either demographic or clinicopathologic parameters (Lapthanasupkul et al., 2020).  Similarly, BRAFV600E mutation were shown to be present in 76% of patients with ameloblastoma in Japan (Seki-Soda et al., 2020). The studies in Europe and South America have also shown similar findings, 46%-62% in the U.S.A. (Brown et al., 2014; Sweeney et al., 2014), 72.2% in Finland and 78.6% in Brazil (do Canto et al., 2019; Kelppe et al., 2019). Interestingly, BRAFV600E mutation in ameloblastoma in other Asian countries had higher rates, with 90% in South Korea and 92% in Iran (Derakhshan et al., 2020; Oh et al., 2019).In contrast, a study in Germany revealed only 25% of BRAFV600E mutations in ameloblastoma (Bartels et al., 2018). Collectively, these studies indicate that the frequency of BRAFV600E mutation in ameloblastoma may vary among geography or ethnic groups (Seki-Soda et al., 2020). The etiology of this variation remains unknown. It is of interest to note that high percentages of BRAFV600E mutation are found in the mandible, while the maxillary ameloblastoma demonstrates the wild-type. (do Canto et al., 2019; Lapthanasupkul et al., 2020; Sweeney et al., 2014).


Besides BRAFV600E mutations, FGFR mutations are also identified, particularly FGFR1 and FGFR3, in almost all human cancers. Specifically, FGFR2 mutations are common in endometrial adenocarcinoma, cholangiocarcinoma, and gastric adenocarcinoma (Weaver et al., 2020). FGFR2 mutations have also been found in ameloblastoma, ranging from 6% to 18% (Brown et al., 2014; Sweeney  et al., 2014). It was suggested that overexpression of FGFR2 plays an important role in the tumor invasion and recurrences of ameloblastoma (Tang and Ji, 2017). Currently, an immunohistochemical investigation demonstrates the overexpression of FGFR2 in ameloblastoma, showing an intense cytoplasmic staining in the peripheral ameloblast-like cells and mild cytoplasmic staining in some central stellate reticulum-like cells (unpublished data) (Figure 2).



Figure 2. The immunostaining of FGFR2 in the follicles of ameloblastoma showing intense cytoplasmic staining in the peripheral ameloblast-like cells (an arrowand weaker staining in the central stellate reticulum-like cells (an arrowhead) (Original magnification 100x).


Mutation of downstream genes in the FGF-MAPK signaling pathway, RAS was identified in approximately 20% of patients with ameloblastoma comprising 8%-15% of KRAS mutations, 6% of both NRAS and HRAS mutations (Brown et al., 2014; Sweeney et al., 2014). RAS mutations are also found in craniofacial syndrome and 20%-25% of all human cancers, including melanoma, non-small cell lung cancer, colorectal cancer, and ovarian cancer (Bromberg-White et al., 2012; Panyavaranant et al., 2019).


Aberrant genes in the FGF-MAPK signaling pathway may play a significant role in the pathogenesis of ameloblastoma. Based on these knowledges, targeted therapies are designed to target these mutated genes intending to help in the treatment for patients with ameloblastoma.


Targeted therapies on ameloblastoma

After the discovery of BRAFV600E mutation in several cancers, many MAPK inhibitors have been designed to target these mutations (Uehling and Harris, 2015). The first BRAF inhibitor targeting BRAFV600E mutation is vemurafenib. Vemurafenib (Zelboraf®) has been approved by the US Food and Drug Administration (FDA) to be used in unresectable or metastatic melanoma with BRAFV600E mutation since 2011 (Kim et al., 2014). The second BRAF inhibitor is dabrafenib (Tafinlar®). It has also been approved by the FDA since 2013. Moreover, dabrafenib has been approved as a combination therapy with trametinib (Mekinist®), a MEK inhibitor (Uehling and Harris, 2015). Apart from vemurafenib and dabrafenib, encorafenib (Braftovi®) has also been approved by the FDA since 2018, and there are several other BRAF inhibitors undergoing development such as MLN-2480, LY-3009120, and PLX8394 (Uehling and Harris, 2015; Degirmenci et al., 2020; Davis and Wayman, 2022). Trametinib, cobimetinib (Cotellic®), and binimetinib (Mektovi®) are MEK inhibitors approved by the FDA to be used as monotherapy or in combination with a BRAF inhibitor in unresectable or metastatic melanoma (Uehling and Harris, 2015; Shirley, 2018). Other MEK inhibitors include selumetinib (Koselugo®), pimasertib, and refametinib (Uehling and Harris, 2015; Markham and Keam, 2020; Tran and Cohen, 2020; Mukhopadhyay et al., 2021). Similarly, ERK inhibitors remain to go through human clinical trial phases (Degirmenci e t al., 2020). Adverse effects of these inhibitors, particularly dermatologic reactions including rash, photosensitivity, and alopecia, have been reported (Welsh and Corrie, 2015). Minor adverse effects include arthralgia, hepatotoxicity, and secondary malignancy (Hagen and Trinh, 2014; Welsh and Corrie, 2015).


Besides MAPK inhibitors, targeted therapies specific for FGFR, including tyrosine kinase inhibitors (TKIs), neutralizing monoclonal antibodies (mAbs) against FGFR, and FGF traps have also been used in various human cancers, for example, breast cancer, gastric cancer, lung cancer, thyroid cancer, and ovarian cancer (Babina and Turner, 2017; Xie et al., 2020). TKIs are divided into 2 groups: non-selective TKIs/multi-targeting TKIs and selective TKIs (Xie et al., 2020). TKIs are ATP-competitive molecules activated by binding to tyrosine kinase domains, resulting in inhibition of autophosphorylation of the receptor (Chae et al., 2017). Non-selective TKIs are the first-generation of targeted therapy strategized to block FGFs signaling. Subsequently, several non-selective TKIs such as lenvatinib (Lenvima®), lucitanib, nintedanib (Ofev®), dovitinib (Novartis®), and ponatinib (Iclusig®) have been developed. Moreover, many non-selective TKIs are currently undertaken for preclinical and clinical phases (Goodman et al., 2007; Nguyen and Shayahi, 2013; Fala, 2015; Babina and Turner, 2017; Chae et al., 2017; Aljubran et al., 2019; Nair et al., 2021; Xie et al., 2020). However, these non-selective TKIs have caused many adverse effects due to the fact that their activity may be against other tyrosine kinase receptors such as vascular endothelial growth factor (VEGF) receptor. These could lead to unfavorable adverse effects, including cardiotoxicity, proteinuria, skin reactions, and digestive disorders (Babina and Turner, 2017; Kommalapati et al., 2021). To reduce adverse effects caused by non-selective TKIs, selective TKIs have therefore been developed to specifically target FGFR (Babina and Turner, 2017; Chae et al., 2017). Erdafitinib (Balversa®), pemigatinib (Pemazyre®), AZD4547, BGJ398, and PD173074 are examples of selective TKIs (Babina and Turner, 2017; Chae et al., 2017; Weaver et al., 2020). Thus far, there are only two FGFRs inhibitors approved by FDA: erdafitinib and pemigatinib (Weaver et al., 2020) (Table 2).


Table 2. MAPK inhibitors and tyrosine kinase inhibitors.  





BRAF inhibitors



Approved by FDA to use in unresectable or
    metastatic melanoma with BRAFV600E    

Kim et al.,  2014


Dabrafenib (Tafinlar®)

Approved by FDA to use in unresectable or
    metastatic melanoma with BRAFV600E
    mutation (as a single agent or
    combination with Trametinib)

Uehling and Harris, 2015


Encorafenib (Braftovi®)

Approved by FDA to use in combination for
    patients with unresectable or metastatic
    melanoma with BRAFV600E mutation

Davis and Wayman, 2022



Ongoing clinical trials

Uehling and Harris, 2015



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials


TAK 632

Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials

MEK inhibitors

Trametinib (Mekinist®)

Approved by FDA to use with patients with
    metastatic melanoma with V600E/K
    mutation (monotherapy or combination
    with dabrafenib)

Uehling and Harris, 2015


Cobimetinib (Cotellic®)


Approved by FDA to use with patients with
    metastatic melanoma with V600E/K
    mutation (monotherapy or combination
    with vemurafenib)

Uehling and Harris, 2015


Binimetinib (Mektovi®)


Approved by FDA to use with patients with
    metastatic melanoma with V600E/K
    mutation (monotherapy or combination
    with encorafenib)

Shirley, 2018


Selumetinib (Koselugo®))

Approved by FDA to use for patients with

Markham and Keam,  2022



Ongoing clinical trials

Uehling and Harris, 2015



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials

ERK inhibitors


Ongoing clinical trials

Uehling and Harris, 2015



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials

Non-selective TKIs


Ongoing clinical trials

Xie et al., 2020


Nintedanib (Ofev®)

Approved by FDA

Fala, 2015


Dovitinib (Novartis®)

Ongoing clinical trials

Xie et al., 2020


Regorafenib (Stivarga®)

Approved by FDA

Aljubran et al., 2019



Ongoing clinical trials

Xie et al., 2020


Ponatinib (Iclusig®)

Approved for market

Xie et al., 2020


Lenvatinib (Lenvima®)

Approved by FDA

Nair et al.,  2021


Pazopanib (Votrient®)

Approved by FDA

Nguyen and Shayahi,  2013



Ongoing clinical trials

Xie et al., 2020


Sunitinib (Sutent®)

Approved by FDA

Goodman et al., 2007



Ongoing clinical trials

Xie et al., 2020

Selective TKIs

Erdafitinib (Balversa®)

Approved by FDA

Weaver et al., 2020


Pemigatinib (Pemazyre®)

Approved by FDA

Weaver et al., 2020



Ongoing clinical trials

Xie et al.,  2020



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials



Ongoing clinical trials





Immunotherapy using neutralizing monoclonal antibodies appears to be more effective and less toxic than TKIs. These may be due to the specificity of antibody-antigen interactions. Bemarituzumab, GP369, and BAY1187982 are examples of mAb specifically targeting FGFR2 (Babina and Turner, 2017; Chae et al., 2017). FGF traps are alternative molecules strategized to block the activity of the FGF-MAPK signaling pathway by binding the molecules to the FGF ligands. FP-1039, SM27, and NSC12 are examples of FGF traps tested in ongoing human clinical trials (Babina and Turner, 2017; Chae et al., 2017; Xie et al., 2020).


Although there have been several investigations of MAPK and FGFR inhibitors used for treating ameloblastoma, randomized controlled trials of these inhibitors in patients with ameloblastoma have not been studied. Only a few case reports have been undertaken with promising results. For example, BRAF and MEK inhibitors including, vemurafenib, dabrafenib, and trametinib in ameloblastoma cases with BRAFV600E mutation have shown a significant reduction in tumor sizes (Kaye et al., 2015; Faden and Algazi, 2016; Tan et al., 2016; Fernandes et al., 2018; Brunet et al., 2019). Moreover, lenvatinib and erdafitinib revealed a remarkable reduction in tumor sizes in ameloblastoma cases with FGFR2 mutation (Lawson-Michod et al., 2022; Weaver et al., 2020). Therefore, the using of BRAF, MEK, and FGFR inhibitors in the treatment of ameloblastoma are recommended. However, there is only one case report that showed no response to using trametinib in a 13-year-old female with mutated BRAF ameloblastoma. Further studies on the efficacy and appropriate dosage for trametinib for BRAF mutated ameloblastoma were then suggested (Daws et al., 2021) (Table 3).


Table 3. Case reports using targeted therapies in patients with ameloblastoma. 









Kaye et al., 2014



Recurrent ameloblastoma with pulmonary metastases

Left mandible
and bilateral lung


dabrafenib + trametinib

Decreased tumor size
and metastases

Tan et al., 2016



Primary ameloblastoma

Left mandible



Decreased tumor size with skin lesion (actinic keratosis)

Faden et al., 2017



Recurrent ameloblastoma

Right mandible



Decreased tumor size

Fernandes et al., 2018



Recurrent ameloblastoma

Left mandible



Decreased tumor size

Brunet et al., 2019



Metastatic ameloblastoma

Bilateral lung


Dabrafenib + trametinib

Complete remission

Weaver et al., 2020



Primary ameloblastoma

Right maxilla



Decreased tumor size

Daws et al., 2021



Primary ameloblastoma

Right mandible



Failed response

Lawson-Michod et al., 2022



Recurrent ameloblastoma

Right pterygopalatine fossa, skull base, and maxilla



Decreased tumor size


Although treatment of ameloblastoma with BRAF and MEK inhibitors and TKI have been investigated, using ERK inhibitors for treatment of ameloblastoma have never been explored. Further studies on the use of ERK inhibitors may warrant benefits to patients with mandibular ameloblastoma. 



Recent data have revealed that gene mutations in the FGF-MAPK signaling pathway including BRAFV600E, FGFR2, and RAS play a crucial role in the pathogenesis of ameloblastoma particularly in the mandible. Current treatment of ameloblastoma remains aggressive surgical resection in order to prevent recurrences. The results of this treatment modality enormously impact the quality of life of the patients. Targeted therapy aiming to inhibit specific altered proteins in the FGF-MAPK signaling pathway may be used as an adjuvant treatment along with the surgical approaches which may help minimize complications after treatment and provide the better quality of patients’ lives. Targeted therapies in ameloblastoma are therefore envisaged as a promising novel treatment modality for ameloblastoma.



The authors are grateful to Research Funding for graduate students, Faculty of Dentistry and Chiang Mai University Presidential Scholarship, Chiang Mai University, Thailand for providing financial support.



All authors assisted in the data researching, analyzing, and summarizing. Nattanit Boonsong and Anak Iamaroon conducted all of the reviewing processes and wrote the manuscript. All authors have read and approved of the final manuscript.



The authors declare no conflict of interest.



Aljubran A., Elshenawy, M.A., Kandil, M., Zahir, M.N., Shaheen, A., Gad, A., Alshaer, O., Alzahrani, A., Eldali, A., and Bazarbashi, S. 2019. Efficacy of regorafenib in metastatic colorectal cancer: A multi-institutional retrospective study. Clinical Medicine Insights: Oncology. 13:1179554918825447.


Babina, I.S., Turner, N.C. 2017. Advances and challenges in targeting FGFR signalling in cancer. Nature Reviews Cancer. 17:318-332.


Bartels, S., Adisa, A., Aladelusi, T., Lemound, J., Stucki-Koch, A., Hussein, S., Kreipe, H., Hartmann, C., Lehmannm, U., and Hussein, K. 2018. Molecular defects in braf wild-type ameloblastomas and craniopharyngiomas-differences in mutation profiles in epithelial-derived oropharyngeal neoplasms. Virchows Archiv. 472: 1055-1059.


Bromberg-White, J.L., Andersen, N.J., and Duesbery, N.S. 2012. Mek genomics in development and disease. Briefings in Functional Genomics. 11: 300-310.


Brown, N.A. and Betz, B.L. 2015. Ameloblastoma: A review of recent molecular pathogenetic discoveries. Biomarkers in Cancer. 7s2: BIC.S29329.


Brown, N.A., Rolland, D., McHugh, J.B., Weigelin, H.C., Zhao, L., Lim, M.S., Elenitoba-Johnson, K.S., and Betz, B.L. 2014. Activating fgfr2-ras-braf mutations in ameloblastoma. Clinical Cancer Research. 20: 5517-5526.


Brunet, M., Khalifa, E., and Italiano, A. 2019. Enabling precision medicine for rare head and neck tumors: The example of braf/mek targeting in patients with metastatic ameloblastoma. Frontiers in Oncology. 9:1204.


Burotto, M., Chiou, V.L., Lee, J.M., and Kohn, E.C. 2014. The mapk pathway across different malignancies: A new perspective. Cancer. 120: 3446-3456.


Chae, Y.K., Ranganath, K., Hammerman, P.S., Vaklavas, C., Mohindra, N., Kalyan, A., Matsangou, M., Costa, R., Carneiro, B., Villaflor, V.M., et al. 2017. Inhibition of the fibroblast growth factor receptor (fgfr) pathway: The current landscape and barriers to clinical application. Oncotarget. 8: 16052-16074.


Chang, F., Steelman, L.S., Lee, J.T., Shelton, J.G., Navolanic, P.M., Blalock, W.L., Franklin, R.A., and McCubrey, J.A. 2003. Signal transduction mediated by the ras/raf/mek/erk pathway from cytokine receptors to transcription factors: Potential targeting for therapeutic intervention. Leukemia. 17: 1263-1293.


Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., et al. 2002. Mutations of the braf gene in human cancer. Nature. 417: 949-954.


Davis, J. and Wayman, M. 2022. Encorafenib and binimetinib combination therapy in metastatic melanoma. Journal of the Advanced Practitioner in Oncology. 13: 450-455.


Daws, S., Chaiyasate, K., and Lehal, A. 2021. Treatment of a braf v600e positive ameloblastoma in a pediatric patient with mek inhibitor monotherapy. FACE. 2: 179-182.


Degirmenci, U., Wang, M., and Hu, J. 2020. Targeting aberrant ras/raf/mek/erk signaling for cancer therapy. Cells. 9: 198.


Derakhshan, S., Aminishakib, P., Karimi, A., Saffar, H., Abdollahi, A., Mohammadpour, H., Kharazi Fard, M.J., and Memarha, A. 2020. High frequency of braf v600e mutation in Iranian population ameloblastomas. Medicina Oral, Patologia Oral, Cirugia Bucal. 25: e502-e507.


Dhanuthai K., Chantarangsu S., Rojanawatsirivej S., Phattarataratip E., Darling M., Jackson-Boeters L., Said-Al-Naief N., Shin H.I., An C.H., Hong N.T. et al. 2012. Ameloblastoma: A multicentric study. Oral Surgery, Oral Medicine, Oral Pathology, and Oral Radiology. 113: 782-788.


Dhillon, A.S., Hagan, S., Rath, O., and Kolch, W. 2007. Map kinase signalling pathways in cancer. Oncogene. 26: 3279-3290.


do Canto, A.M., da Silva Marcelino, B.M.R., Schussel, J.L., Wastner, B.F., Sassi, L.M., Corrêa, L., de Freitas, R.R., Hasséus, B., Kjeller, G., Junior, C.A.L., et al. 2019. Immunohistochemical analysis of braf v600e mutation in ameloblastomas. Clinical Oral Investigations. 23: 779-784.


Effiom, O.A., Ogundana, O.M., Akinshipo, A.O., and Akintoye, S.O. 2018. Ameloblastoma: Current etiopathological concepts and management. Oral Diseases. 24: 307-316.


El-Naggar, A.K., Chan, J.K.C., Grandis, J.R., Takata, T., and Slootweg, P.J. 2017. WHO classcification of haed and neck tumors. International Agency for Research on Cancer (IARC).


Faden, D.L. and Algazi, A. 2016. Durable treatment of ameloblastoma with single agent brafi re: Clinical and radiographic response with combined braf-targeted therapy in stage 4 ameloblastoma. Journal of the National Cancer Institute. 109: djw190.


Fala, L. 2015. Ofev (nintedanib): first tyrosine kinase inhibitor approved for the treatment of patients with idiopathic pulmonary fibrosis. American Health & Drug Benefits. 8(Spec Feature): 101-104.


Fernandes, G.S., Girardi, D.M., Bernardes, J.P.G., Fonseca, F.P., and Fregnani, E.R. 2018. Clinical benefit and radiological response with braf inhibitor in a patient with recurrent ameloblastoma harboring v600e mutation. BMC Cancer. 18: 887.


Goodman, V.L., Rock, E.P., Dagher, R., Ramchandani, R.P., Abraham, S., Gobburu, J.V., Booth, B.P., Verbois, S.L., Morse, D.E., Liang, CY., et al. 2007. Approval summary: Sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clinical Cancer Research. 13: 1367-1373.


Gültekin, S.E., Aziz, R., Heydt, C., Sengüven, B., Zöller, J., Safi, A.F., Kreppel, M., and Buettner, R. 2018. The landscape of genetic alterations in ameloblastomas relates to clinical features. Virchows Archiv: An International Journal of Pathology. 472: 807-814.


Guo, Y.J., Pan, W.W., Liu, S.B., Shen, Z.F., Xu, Y., and Hu, L.L. 2020. Erk/mapk signalling pathway and tumorigenesis. Experimental and Therapeutic Medicine. 19: 1997-2007.


Hagen, B. and Trinh, V.A. 2014. Managing side effects of vemurafenib therapy for advanced melanoma. Journal of the Advanced Practitioner in Oncology. 5: 400-410.


Johnson, G.L., Stuhlmiller, T.J., Angus, S.P., Zawistowski, J.S., and Graves, L.M. 2014. Molecular pathways: Adaptive kinome reprogramming in response to targeted inhibition of the braf-mek-erk pathway in cancer. Clinical Cancer Research. 20: 2516-2522.


Junttila, M.R., Li, S.P., and Westermarck, J. 2008. Phosphatase-mediated crosstalk between mapk signaling pathways in the regulation of cell survival. ASEB Journal. 22: 954-965.


Katoh, M. and Nakagama, H. 2014. Fgf receptors: Cancer biology and therapeutics. Medicinal Research Reviews. 34: 280-300.


Kaye, F.J., Ivey, A.M., Drane, W.E., Mendenhall, W.M., and Allan, R.W. 2015. Clinical and radiographic response with combined braf-targeted therapy in stage 4 ameloblastoma. Journal of the National Cancer Institute. 107: 378.


Kelppe, J., Thorén, H., Ristimäki, A., Haglund, C., Sorsa, T., and Hagström, J. 2019. Braf v600e expression in ameloblastomas-a 36-patient cohort from helsinki university hospital. Oral Diseases. 25: 1169-1174.


Keshet, Y. and Seger, R. 2010. The map kinase signaling cascades: A system of hundreds of components regulates a diverse array of physiological functions. Methods in Molecular Biology. 661: 3-38. 


Kim, G., McKee, A.E., Ning, Y.M., Hazarika, M., Theoret, M., Johnson, J.R., Xu, Q.C., Tang, S., Sridhara, R., Jiang, X., et al. 2014. FDA approval summary: Vemurafenib for treatment of unresectable or metastatic melanoma with the brafv600e mutation. Clinical Cancer Research. 20: 4994-5000.


Kommalapati, A., Tella, S.H., Borad, M., Javle, M., and Mahipal, A. 2021. Fgfr inhibitors in oncology: Insight on the management of toxicities in clinical practice. Cancers (Basel). 13: 2968.


Konchanthes, S. and Chamusi, N. 2018. Desmoplastic ameloblastoma: A report of two cases. Chiang Mai Dental Journal. 39: 127-136.


Lapthanasupkul, P., Laosuk, T., Ruangvejvorachai, P., Aittiwarapoj, A., and Kitkumthorn, N. 2020. Frequency of braf v600e mutation in a group of thai patients with ameloblastomas. Oral Surgery, Oral Medicine, Oral Pathology, and Oral Radiology. 132: e180-e185.


Lawson-Michod, K.A., Le, C.H., Tranesh, G., Thomas, P.C., and Bauman, J.E. 2022. Precision medicine: Sustained response to erdafitinib in fgfr2-mutant, multiply recurrent ameloblastoma. Cancer Reports (Hoboken).e1656.


Liu, F., Yang, X., Geng, M., and Huang, M. 2018. Targeting erk, an achilles' heel of the mapk pathway, in cancer therapy. Acta Pharmaceutica Sinica B. 8: 552-562.


Markham, A. and Keam, S.J. 2020. Selumetinib: first approval. Drugs. 80: 931-937.


Matallanas, D., Birtwistle, M., Romano, D., Zebisch, A., Rauch, J., von Kriegsheim, A., and Kolch, W. 2011. Raf family kinases: Old dogs have learned new tricks. Genes Cancer. 2: 232-260.


Mukhopadhyay, S., Maitra, A., and Choudhury, S. 2021. Selumetinib: The first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma. Current Medical Research and Opinion. 37: 789-794.


Nair, A., Reece, K., Donoghue, M.B, Yuan, W.V., Rodriguez, L., Keegan, P., and Pazdur, R. 2021. Fda supplemental approval summary: Lenvatinib for the treatment of unresectable hepatocellular carcinoma. Oncologist. 26: e484-e491.


Neville, B.W., Damm, D.D., Allen, C.M., and AC, C. 2016. Odontogenic cysts and tumors. Oral and maillofacial pathology. 4 ed. Elsevier. p. 632-689.


Nguyen, D.T. and Shayahi, S. 2013. Pazopanib: Approval for soft-tissue sarcoma. Journal of the Advanced Practitioner in Oncology. 4: 53-57.


Oh, K.Y., Cho, S.D., Yoon, H.J., Lee, J.I., Ahn, S.H., and Hong, SD. 2019. High prevalence of braf v600e mutations in korean patients with ameloblastoma: Clinicopathological significance and correlation with epithelial-mesenchymal transition. Journal of Oral Pathology & Medicine. 48: 413-420.


Ornitz, D.M. and Itoh, N. 2015. The fibroblast growth factor signaling pathway. Wiley Interdisciplinary Reviews: Developmental Biology. 4: 215-266.


Panyavaranant, P., Teerapakpinyo, C., Pohthipornthawat, N., Oranratanaphan, S., Shuangshoti, S., and Triratanachat, S. 2019. Ras mutation in mucinous carcinoma of the ovary. Asian Pacific Journal of Cancer Prevention. 20: 1127-1132.


Ranjbari, N., Almasi, S., Mohammadi-asl, J., and Rahim, F. 2013. Braf mutations in Iranian patients with papillary thyroid carcinoma. Asian Pacific Journal of Cancer Prevention. 14: 2521-2523.


Saghravanian, N., Salehinejad, J., Ghazi, N., Shirdel, M., and Razi, M. 2016. A 40-year retrospective clinicopathological study of ameloblastoma in Iran. Asian Pacific Journal of Cancer Prevention. 17: 619-623.


Sandoval, S/, Pigazzi, M., and Sakamoto, K.M. 2009. Creb: A key regulator of normal and neoplastic hematopoiesis. Advances in Hematology. 2009: 634292.


Schreiber, M., Kolbus, A., Piu, F., Szabowski, A., Möhle-Steinlein, U., Tian, J., Karin, M., Angel, P., and Wagner, E.F. 1999. Control of cell cycle progression by c-jun is p53 dependent. Genes & Development. 13: 607-619.


Seki-Soda, M., Sano, T., Ito, K., Yokoo, S., and Oyama, T. 2020. An immunohistochemical and genetic study of braf(v600e) mutation in japanese patients with ameloblastoma. Pathology International. 70: 224-230.


Shirley, M. 2018. Encorafenib and binimetinib: first global approvals. Drugs. 78: 1277-1284.


Simanshu, D.K., Nissley, D.V., and McCormick, F. 2017. Ras proteins and their regulators in human disease. Cell. 170: 17-33.


Sweeney, R.T., McClary, A.C., Myers, B.R., Biscocho, J., Neahring, L., Kwei, K.A., Qu, K., Gong, X., Ng, T., Jones, C.D., et al. 2014. Identification of recurrent smo and braf mutations in ameloblastomas. Nature Genetics. 46: 722-725.


Tan, S., Pollack, J.R., Kaplan, M.J., Colevas, A.D., and West, R.B. 2016. Braf inhibitor treatment of primary braf-mutant ameloblastoma with pathologic assessment of response. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 122: e5-e7.


Tang, Y. and Ji, T. 2017. Expression of fibroblast growth factor receptor type 2 in primary and recurrent ameloblastoma are correlated with ameloblastoma clinic characteristics. International Journal of Oral and Maxillofacial Surgery. 46(Supplement 1): 315.


Tran, B. and Cohen, M.S. 2020. The discovery and development of binimetinib for the treatment of melanoma. Expert Opinion on Drug Discovery 15: 745-754.


Turner, N. and Grose, R. 2010. Fibroblast growth factor signalling: From development to cancer. Nature Reviews Cancer. 10: 116-129.


Uehling, D.E. and Harris, P.A. 2015. Recent progress on map kinase pathway inhibitors. Bioorganic & Medicinal Chemistry Letters. 25: 4047-4056.


Weaver, A.N., Francisque, F., and Bowles, D.W. 2020. Tumor regression after treatment with lenvatinib in fgfr2-mutated ameloblastoma. JCO Precision Oncology. 4: 1403-1406.


Welsh, S.J. and Corrie, P.G. 2015. Management of braf and mek inhibitor toxicities in patients with metastatic melanoma. Therapeutic Advances in Medical Oncology. 7: 122-136.


Xie, Y., Su, N., Yang, J., Tan, Q., Huang, S., Jin, M., Ni, Z., Zhang, B., Zhang, D., Luo, F., et al. 2020. FGF/FGFR signaling in health and disease. Signal Transduction and Targeted Therapy. 5, 181.


You, Z., Liu, S.P., Du, J., Wu, Y.H., and Zhang, S.Z. 2019. Advancements in mapk signaling pathways and mapk-targeted therapies for ameloblastoma: a review. Journal of Oral Pathology & Medicine. 48: 201-205.

OPEN access freely available online

Chiang Mai University Journal of Natural Sciences [ISSN 16851994]

Chiang Mai University, Thailand.

Nattanit Boonsong1, Kittipong Laosuwan2, Nakarin Kitkumthorn3, Puangwan Lapthanasupkul4, Wacharaporn Thosaporn2, and Anak Iamaroon2, 5, *


1 Graduate PhD Program in Oral Science, Faculty of Dentistry, Chiang Mai University, under the CMU Presidential Scholarship, Thailand.

2 Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.

3 Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand.

4 Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand.

5 Excellence Center in Osteology Research and Training Center (ORTC), Chiang Mai University, Chiang Mai, 50200, Thailand.


Corresponding author: Anak Iamaroon, E-mail:

Total Article Views

Editor: Wasu Prathum-Aree,

Chiang Mai University, Thailand


Article history:

Received: May 3, 2022;

Revised: July 22, 2022;

Accepted: August 11, 2022;

Published online: August 22, 2022