Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma

Abstract

Thyroid cancer is generally curable and, in many cases, can be completely treated, although it can sometimes recur after cancer therapy. Papillary thyroid cancer (PTC) is known as one of the most general subtypes of thyroid cancer, which take up nearly 80% of whole thyroid cancer. However, PTC may develop anti-cancer drug resistance via metastasis or recurrence, making it practically incurable. In this study, we propose a clinical approach that identifies novel candidates based on target identification and validation of numerous survival-involved genes in human sorafenib-sensitive and -resistant PTC. Consequently, we recognized a sarco/endoplasmic reticulum calcium ATPase (SERCA) in human sorafenib-resistant PTC cells. Based on the present results, we detected novel SERCA inhibitor candidates 24 and 31 via virtual screening. These SERCA inhibitors showed remarkable tumor shrinkage in the sorafenib-resistant human PTC xenograft tumor model. These consequences would be clinically worthwhile for the development of a new combinatorial strategy that effectively targets incredibly refractory cancer cells, such as cancer stem cells and anti-cancer drug-resistant cells.