First insights for targeted therapies in odontogenic myxoma
- 40 Downloads
Odontogenic myxoma (OM) occasionally responds poorly to surgical treatment. The MAPK pathway is constitutively activated in several neoplasms and we aimed to test if the MAPK pathway is activated in OM, in order to pave the way for an alternative therapy for aggressive and recurrent cases.
Materials and methods
The immunoexpression of phosphorylated ERK1/2 (pERK1/2) was assessed in OM. We established a 3D organotypic culture model for the in vitro study and patient-derived xenografts (PDX) in mice for the in vivo study. The MEK inhibitor U0126 was used to inhibit phosphorylation of ERK1/2 in the in vitro and in vivo models.
All OM showed strong pERK1/2 immunoexpression, consistent with MAPK pathway activation. Treatment of the 3D culture with U0126 resulted in a reduced pERK1/2/ERK1/2 ratio. Consistent with the in vitro results, all PDX of animals treated with U0126 showed a decreased volume fold change compared with controls.
The MAPK pathway is activated in OM and its inhibition leads to tumor shrinkage in PDX and cell culture models.
Our results offer a pre-clinical frame for OM-targeted therapy. Further work is needed to determine if this initial finding holds clinical promise.
KeywordsOdontogenic tumors MEK inhibition Targeted therapy ERK MAPK pathway 3D cell culture PDX
Núbia Braga Pereira: Original draft preparation, worked on the experiments and revision of the final version of the manuscript
Victor Coutinho Bastos: Worked on the experiments and revision of the final version of the manuscript
Juliana Cristina de Souza: Worked on the experiments and revision of the final version of the manuscript
Marina Gonçalves Diniz: Data analyses and revision of the final version of the manuscript
Jéssica Gardone Vitório: Worked on the experiments and revision of the final version of the manuscript
Gregory Thomas Kitten: Data analyses and revision of the final version of the manuscript
Luciana de Oliveira Andrade: Data analyses and revision of the final version of the manuscript
Gleide Fernandes de Avelar: Data analyses and revision of the final version of the manuscript
Wagner Henriques Castro: Data acquisition and revision of the final version of the manuscript
Vanessa Fátima Bernardes: Data analyses and revision of the final version of the manuscript
Adriana Abalen Martins Dias: Data analyses and revision of the final version of the manuscript
Ricardo Santiago Gomez: Data analyses and revision of the final version of the manuscript
Carolina Cavalieri Gomes: Supervision of the study, original draft preparation, data analyses, and revision of the final version of the manuscript
This study was financed in part by the Coordination for the Improvement of Higher Education Personnel (CAPES)/Brazil, Finance code 001, the National Council for Scientific and Technological Development (CNPq)/Brazil, and the Research Support Foundation of the State of Minas Gerais (FAPEMIG)/Brazil. NBP receive CAPES scholarship. RSG and CCG are research fellows at CNPq.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The study was approved by the University Ethics Committee (Protocol CAAE 48121415.2.0000.5149) and by the University Ethics Committee on the Use of Animals (Protocol 201/2015). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from individual participants included in the study.
- 2.El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (2017) WHO Classification of Head and Neck Tumours (4th Edition), IARC, Lyon.Google Scholar
- 3.Gomes CC, Diniz MG, Duarte AP, Bernardes VF, Gomez RS (2011) Molecular review of odontogenic myxoma. Oral Oncol 47(5):325–328. https://doi.org/10.1016/j.oraloncology.2011.03.006 CrossRefPubMedGoogle Scholar
- 7.Diniz MG, Gomes CC, de Sousa SF, Xavier GM, Gomez RS (2017) Oncogenic signaling pathways in benign odontogenic cysts and tumours. Oral Oncol 72:165–173. https://doi.org/10.1016/j.oraloncology.2017.07.021 CrossRefPubMedGoogle Scholar
- 8.Gomes CC, de Sousa SF, de Menezes GHF, Duarte AP, Pereira Tdos S, Moreira RG, de Castro WH, Villacis RA, Rogatto SR, Diniz MG, Gomez RS (2016) Recurrent KRAS G12V pathogenic mutation in adenomatoid odontogenic tumours. Oral Oncol 56:e3–e5. https://doi.org/10.1016/j.oraloncology.2016.03.001 CrossRefPubMedGoogle Scholar
- 10.Coura BP, Bernardes VF, de Sousa SF, França JA, Pereira NB, Pontes HAR, Batista AC, da Cruz Perez DE, Junior RLCA, Souza LB, Martins MD, Diniz MG, Gomez RS, Gomes CC (2019) KRAS mutations drive adenomatoid odontogenic tumor and are independent of clinicopathological features. Mod Pathol 2019 32(6):799–806. https://doi.org/10.1038/s41379-018-0194-4 CrossRefGoogle Scholar
- 11.Santos JN, Sousa Neto ES, França JA, Diniz MG, Moreira RG, Castro WH, Gomez RS, de Sousa SF, Gomes CC (2017) Next generation sequencing of oncogenes and tumor suppressor genes in odontogenic myxomas. J Oral Pathol Med 46(10):1036–1039. https://doi.org/10.1111/jop.12598.
- 14.Bastos VC, Pereira NB, Diniz MG, Andrade LO, Castro WH, Kitten GT, Gomez RS, Gomes CC (2019) Bringing benign ectomesenchymal odontogenic tumours to the lab: an in vitro study using an organotypic culture model. J Oral Pathol Med 48(2):174–179. https://doi.org/10.1111/jop.12812 CrossRefPubMedGoogle Scholar
- 15.Pearson AT, Finkel KA, Warner K.A et al (2016) Patient-derived xenograft (PDX) tumors increase growth rate with time. Oncotarget 7 (7): 7993-8005. https://doi.org/10.18632/oncotarget.6919.
- 19.Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo G, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT (2018) First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov 8:184–195. https://doi.org/10.1158/2159-8290.cd-17-1119 CrossRefPubMedGoogle Scholar
- 21.Srinivasan R, Zabuawala T, Huang H, Zhang J, Gulati P, Fernandez S, Karlo JC, Landreth GE, Leone G, Ostrowski MC (2009) Erk1 and Erk2 regulate endothelial cell proliferation and migration during mouse embryonic angiogenesis. PLoS One. 4(12):e8283. https://doi.org/10.1371/journal.pone.0008283 CrossRefPubMedPubMedCentralGoogle Scholar