PO-067 Autophagy modulates response to cisplatin in thyroid cancer cells

Introduction Thyroid cancer is the most common endocrine malignancy and, although the death rate of thyroid cancer is relatively low, the recurrence rate of this disease is high. One of the most prevalent mutation in thyroid cancer is V600EBRAF. This mutation causes hiperactivation of the ERK-MAPKs pathway, which leads to a greater cell proliferation, survival and invasion. Nevertheless, the treatment with BRAF inhibitors lacks of efficacy in thyroid cancer, due to development of resistance and important adverse effects in other tissues. Thus, new therapies are required to improve treatment efficiency and specificity in this type of tumours. On the other hand, autophagy is a process whereby the cells recycle their own cellular components and obtain energy, but its role in thyroid cancer is not clarified. In some cases, autophagy is related to a chemotherapy resistance response in cancer cells. We sought to characterise the role of autophagy on survival of anaplastic thyroid cancer cells with V600EBRAF, and to determine the effects of its inhibition on chemosensitivity to cisplatin. Material and methods Human anaplastic thyroid carcinoma cell line BHT-101 was treated with cisplatin in the presence of the autophagy-specific inhibitors bafilomycin A1 (BafA1) and 3-methyladenine (3MA). Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. Western blotting assay was used to investigate autophagy markers levels before cisplatin treatment. Results and discussions Our results show that autophagy plays a protective role in these cells, since its inhibition with BafA1 and 3MA increases cell death. Cisplatin also inhibits cell proliferation and induces cell death, but at lower rate. In addition, cisplatin modulates the expression of autophagy-related proteins LC3-I/II and p62 in BHT101 cells, indicating an increase of autophagic flux, compatible with a self-protection mechanism. Finally, the combined treatment with cisplatin and autophagy inhibitors shows higher effects on cell viability than the individual treatments. Conclusion All this data, suggest that autophagy is a pro-survival mechanism in anaplastic thyroid cancer cells and that its inhibition enhances cisplatin treatment response. Thus, we establish the inhibition of this process as an effective approach in treating of V600EBRAF-expressing thyroid tumours.