Targeting Glycogen Metabolism as a Novel Therapeutic Approach in Anaplastic Thyroid Cancer

Abstract

Effective treatment options for well-differentiated papillary (PTC) and follicular (FTC) thyroid cancers afford positive patient prognoses. The absence of effective interventions for the stem-like, dedifferentiated anaplastic thyroid cancer (ATC) results in poor patient outcomes with a mortality rate higher than all other endocrine cancers combined (1). While receptor tyrosine kinase inhibitors such as sorafenib can extend ATC patient survival, drug resistance and tumor reoccurrence often develop (2). Therefore, there is a critical need for more effective targeted therapies for ATC. Although the cell signaling landscape of ATC tumors is well described, very little is known about tumorigenic adaptations in ATC cellular metabolism. Tumors exhibit an increased consumption of glucose compared to normal tissues to fuel tumor progression. Some cancers meet this high glucose requirement by storing and breaking down glycogen. In our studies here, we show for the first time that normal thyroid, PTC, FTC, and ATC cells express genes necessary for glycogen metabolism. We confirm these observations in patient samples in normal thyroid and thyroid cancer patient samples via immunofluorescence in tissue microarrays. Furthermore, we detect intracellular glycogen stores in cell lines representing normal thyroid, PTC, FTC, and ATC cells. Importantly, we demonstrate that glycogen phosphorylase inhibitors result in accumulation of intracellular glycogen and induce subsequent apoptosis in ATC cells. We further show that glycogen phosphorylase inhibitors synergize with kinase inhibitors such as sorafenib and buparlisib to decrease ATC cell viability. Our work establishes glycogen metabolism as a novel metabolic process in thyroid cells that is associated with thyroid cancer dedifferentiation and provides insight to the effectiveness of inhibiting glycogen metabolism as a therapeutic strategy in ATC.