Abstract 330: SGK1 activation is essential for PI3K-dependent tumor development

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.330-330
• Main Authors: Orlacchio, Arturo, Cristofano, Antonio Di
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-330

The PI3K signaling cascade is frequently activated in human cancer, with AKT being commonly considered its major transforming conduit. Conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K pathway, which causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. Concomitant loss of p53 or activation of KRAS dramatically accelerates the development of aggressive and lethal tumors. The PDK1 kinase plays a key role in the PI3K signaling cascade, directly activating, in a PI3K-dependent manner, not only AKT but also a set of additional AGC kinases, including, S6K, PKC, and SGK. Using in vivo, ex vivo, and in vitro genetic and pharmacological approaches, we now show that AKT activation is not sufficient to transform thyroid epithelial cells. Concomitant activation of additional PDK1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo, in mouse models based on Pten loss, alone and in combination with additional genetic alterations. In particular, we show that one member of the SGK family, SGK1, is an essential mediator of the transformation process downstream of PI3K. Genetic and pharmacological SGK1 inhibition strongly reduces cell proliferation in Pten-/-and PIK3CA-mutant cell lines. Moreover we show that concomitant SGK inhibition significantly increases the efficacy of inhibitors targeting AKT or PI3K. Taken together, our data identify an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells. Citation Format: Arturo Orlacchio, Antonio Di Cristofano. SGK1 activation is essential for PI3K-dependent tumor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 330. doi:10.1158/1538-7445.AM2017-330