Erk dimers inhibition is a therapeutic target in thyroid cancer

Abstract

Thyroid carcinoma is the most common endocrine malignancy, and its incidence is rapidly rising in the world. Its initiation and progression involves multiple genetic and epigenetic alterations whereby BRAF and RAS mutations lead to the activation of the ERK signaling pathway. Recently, significant advances have been accomplished by developing pharmacological agents directed against the kinases of the RAS-ERK pathway. However, most of the molecules tested have undesired side effects and promote drug resistance. Consequently, it is imperative to find alternative RAS-ERK pathway inhibitors. It has been shown that by inhibiting ERKs dimerization it is possible to suppress tumor progression. DEL22379, a small molecule inhibitor for ERK dimerization, has been identified to impede the growth of melanoma tumor cells driven by RAS-ERK pathway oncogenes, without affecting ERK phosphorylation (Cancer Cell 28:17082 2015). The aim of this work is to study the role played by ERK dimerization and its inhibition using DEL22379 in thyroid cancer progression. We have used an in vitro model of thyroid tumor cells harboring oncogenic drivers (RAS or BRAF) to complete viability, migration and invasion assays as well as an orthotopic mouse model with anaplastic cells as an in vivo model. We observed that in BRAF mutated cells, ERK dimer formation is sustained for longer compared to the RAS mutated or control cells, resulting in the altered activation of the effected signaling pathway. RAS mutated cells are resistant to DEL22379 in vitro, while BRAF mutated cells are not able to form ERK dimers upon inhibitor addition. Consequently, these cells lose their invasive and migratory potential as well as displaying low viability. Preliminary results suggest DEL22379 treatment inhibits tumor growth in orthotopic mice. These results describe a new molecule that could be effectively used as a therapy in thyroid cancers harboring BRAF or RAS mutated genes. We have observed it is able to partially revert the tumorigenic phenotype, which may result in an improved prognosis in thyroid cancer patients.