Antitumor activity of the ERK inhibitor DEL22379 against BRAF-like cells in thyroid cancer

Abstract

Thyroid cancer is the most prevalent human carcinoma of endocrine origin and its incidence is continuously increasing. Around 80% of all the somatic mutations are accumulated in only five driver genes (BRAF, H/N/K-RAS and RET) which converge in the hyperactivation of the MAPK signalling pathway. Given the central role of this pathway in thyroid tumorigenesis, thyroid cancer research is focused on the identification of new drugs that inhibit the different kinases of the pathway. DEL22379 is an inhibitor of ERK dimerization previously characterized in melanoma and colorectal cancer-derived cell lines as a new approach to partially inhibit ERK activation. It has been reported that ERK dimerization contributes to the activation of ERK cytoplasmic effectors, such as RSK, and enhances malignant cell features. Our objective was to analyse the antitumor effect of the inhibitor of ERK dimerization DEL22379 as a possible therapeutic compound in thyroid cancer. In vitro assays were made with different thyroid cancer cell lines with mutations in BRAF, H/N/K-RAS or RET. To evaluate cell proliferation, migration and invasion; we have used cell cycle, wound healing and matrigel invasion assays, respectively. We also have developed an orthotopic mouse model of anaplastic thyroid cancer by the generation of the 8505c-luc cell line. In vivo tumour progression was monitored by measuring luciferase activity. Treatment with DEL22379 impairs ERK dimers formation in BRAF-like thyroid cells whereas Ras-like cells were unaffected. Unlike melanoma, phosphorylated ERK levels were substantially reduced after treatment with the inhibitor. Inhibition of ERK dimerization and phosphorylation correlated with diminished RSK phosphorylation. We also observed a decrease in cell proliferation, migration and invasion in the anaplastic thyroid cell lines 8505c and OCUT2. DEL22379 treatment significantly reduced tumour growth and formation of lung metastases in an orthotopic mouse model. We propose DEL22379 as a new effective molecule for the inhibition of MAPK signalling and the reduction of cell malignant behaviour, tumour growth and metastasis in vivo, specifically in BRAF-like thyroid tumours. It promises to be another step forward in the achievement to cure thyroid cancer.