The unresponsiveness of anaplastic thyroid carcinomas (ATCs) to multimodal therapy represents the major challenge in thyroid cancer treatment. Our group previously showed that genes involved in cell cycle are differentially expressed in ATCs compared to normal thyroid, and that the most common mutations found in these tumours are related with proliferation and cell cycle genes, namely TP53, RAS, CDKN2A and CDKN2B. Therefore, these genes are promising new targets in ATCs.
Here, we investigated if the inhibition of HRAS by Tipifarnib (TIP) and CDK4/6 by Palbociclib (PD) could be an option in ATC treatment. Different ATCs cell lines with distinct mutational patterns for RAS, CDKN2A and CDKN2B were used to evaluate the cytotoxic effects of these drugs. The IC50 for TIP and PD were determined, and the effects of these compounds in cell cycle, cell death and cell proliferation were analysed.
Cell culture studies demonstrated that low doses of TIP, at 48 h, induced cell cycle arrest in G2/M phase (50%, P<0.01), cell death (20%), and inhibition of cell viability (P<0.001), only in the HRAS mutated cell line. PD at low concentration increased significantly cell cycle arrest on G0/G1 phase (80%, P<0.05), only in cell lines with deletion/mutation in CDKN2A or CDKN2B genes, however only higher doses induced more than 50% of cell death. The inhibition of cell viability was more pronounced in cell lines with deletion/mutation in CDKN2A or CDKN2B genes than in wild type thyroid cancer cell lines or in normal thyroid cells (P<0.05).
In conclusion, this study suggests that TIP and PD, which are currently in clinical trials for other types of cancer, could play a relevant role in inhibiting the progression of ATC, depending on the specific molecular profile of the tumour.
20 - 23 May 2017
European Society of Endocrinology