Abstract 2326: S6K activation is essential for the development of follicular thyroid cancer.

Abstract The PI3K signaling cascade is frequently activated in follicular and anaplastic thyroid tumors. Mice in which the PI3K pathway is constitutively activated through loss of Pten (PtenL/L;TPO-Cre mice) develop thyroid hyperplasia that progresses to thyroid follicular carcinoma. The wide range of downstream targets of this pathway raises the question of the relative role and relevance of its multiple effectors. This issue has important therapeutic implications, since it would be ideal to only target molecules directly involved in the transformation process, thus reducing the toxicity associated with wide-range inhibitors. PDK1 plays a central role in the PI3K cascade, acting as a master regulator of both AKT and S6K. Notably, PDK1 possesses a substrate docking site named “PIF pocket” that is required to phosphorylate and activate S6K but not AKT. In order to define the relative contribution of Akt and S6k to the development of thyroid lesions and to their progression to follicular carcinoma, we have generated a compound mouse strain in which, in addition to thyroid-specific Pten loss, the PIF-pocket site of Pdk1 can be conditionally disrupted by the L155E mutation, resulting in constitutive activation of Akt and mTor, but not of S6k. We have found that young double mutant mice display a significant reduction in thyroid size, compared to PtenL/L;TPO-Cre mice, and that such rescue is associated with a marked decrease in the thyrocytes proliferation rate. More strikingly, while 60% of Pten mutants develop adenomas and carcinomas by one year of age, none of the age-matched double mutant mice displays neoplastic lesions, indicating that Akt activation, in the absence of S6k activation, is completely unable to drive transformation. Furthermore, we have identified STAT3 as a molecule that is selectively activated downstream of S6k, and that is inactive in double mutants. Pharmacological STAT3 inhibition drastically reduces the proliferation rate of thyroid cancer cell lines, suggesting that STAT3 may be one key conduit of S6k oncogenic activity. Citation Format: Valeria Gabriela Antico Arciuch, Antonio Di Cristofano. S6K activation is essential for the development of follicular thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2326. doi:10.1158/1538-7445.AM2013-2326