Targeting inhibitor of apoptosis proteins to treat thyroid cancer

Thyroid cancer is the most common endocrine malignancy and the incidence has tripled over the last three decades. Most patients respond well to current treatments such as radiotherapy, surgery and other therapeutics, however a small percentage become radioiodine refractory, which is associated with worse prognosis and low survival rate. Currently there are tyrosine kinase inhibitors available for radioiodine refractory patients, which target mitogen-activated protein kinase pathway, however they carry adverse significant side effects. TPC1, K1, SW1736 and Nthy-Ori 3-1 cell lines were used in this study. Inhibitor of apoptosis proteins have been a target of interest in cancer therapeutics and SMAC mimetics have shown great potential in cancer therapy. This study aimed to look at the effects of SMAC mimetics on these cell lines as a monotherapy, as well as in combination with tyrosine kinase inhibitor, sorafenib and PPARg agonists  rosiglitazone/retinoic acid, while exploring the signalling pathways in which they work through. Cell proliferation was examined using xCELLigence Real time Cell Analysis assay as well as the HoloMonitor M4. It was found that SMAC mimetics used in combination with sorafenib as well as a PPARg agonist rosiglitazone/retinoic acid displayed more effective results than the SMAC mimetics alone. This suggests redifferentiation of cells may have occurred. The HoloMonitor M4 also showed cells treated with SMAC mimetics alone and in combination with sorafenib and rosiglitazone/retinoic acid displayed morphological and motility changes. Therefore the
results from this study showed that SMAC mimetics in combination with tyrosine kinase inhibitors as well as PPARg agonists could lead to potential novel therapeutics for thyroid
cancer.