Targeting the mTOR Pathway in Hurthle Cell Carcinoma Results in Potent Antitumor Activity
Yiyu Dong, Yongxing Gong, Fengshen Kuo, Vladimir Makarov, Ed Reznik, Gouri J. Nanjangud, Ömer Aras, HuiYong Zhao, Rui Qu, James A. Fagin, Eric J. Sherman, Bin Xu, Ronald Ghossein, Timothy A. Chan, Ian Ganly
Abstract
Hurthle cell carcinomas (HCCs) are refractory to radioactive iodine and unresponsive to chemotherapeutic agents, with a fatality rate that is the highest among all types of thyroid cancer after anaplastic thyroid cancer. Our previous study on the genomic landscape of HCCs identified a high incidence of disruptions of mTOR pathway effectors. Here, we report a detailed analysis of mTOR signaling in cell line and patient-derived xenograft mouse models of HCCs. We show that mTOR signaling is upregulated and that targeting mTOR signaling using mTOR inhibitors suppresses tumor growth in primary tumors and distant metastasis. Mechanistically, ablation of mTOR signaling impaired the expression of p-S6 and cyclin A2, resulting in the decrease of the S phase and blocking of cancer cell proliferation. Strikingly, mTOR inhibitor treatment significantly reduced lung metastatic lesions, with the decreased expression of Snail in xenograft tumors. Our data demonstrate that mTOR pathway blockade represents a novel treatment strategy for HCC.