BET proteins and the MNK-eIF4E pathway crosstalk in thyroid cancer

The incidence rates of thyroid cancer in both women and men have been increasing in recent years. Patients with relapsed advanced differentiated thyroid cancer, which include papillary and thyroid cancers, are treated with kinase inhibitors targeting the anti-angiogenic and the B-raf pathways. However, the success of current drug therapies is limited, and additional novel therapies are needed for these patients. A significant number of differentiated thyroid cancers demonstrate collagen-rich stromal reaction, with increased collagen I expression associated with worse patient outcome. We have found that eukaryotic translation initiation factor 4E (eIF4E), an oncogene that is overexpressed in aggressive thyroid cancers, is required for growth and survival of differentiated thyroid cancer cells in 3D collagen. Importantly, inhibiting bromodomain (BRD) and extra terminal domain (BET) family of proteins, which function as 'readers' of histone acetylation marks, represses eIF4E expression and decreases growth of differentiated thyroid cancer cells in 3D collagen. Paradoxically, treatment of differentiated thyroid cancer cells with BET inhibitors induces eIF4E phosphorylation, the active form of the protein. This finding indicates activation of feedback loops by cancer cells to mitigate the effects of BET inhibitors. Treatment of differentiated thyroid cancer cells with an inhibitor of MNK1/2, which phosphorylate eIF4E, blocks BET inhibitor-induced phosphorylation of eIF4E. Moreover, this combination treatment synergistically block growth of cancer cells in 3D collagen. Our ongoing experiments will characterize the mechanism of increased eIF4E phosphorylation following BET inhibitor treatment and evaluate the effects of co-targeting BET proteins and MNK kinases in vivo on tumor growth.