TY - JOUR
T1 - SGK1 is a critical component of an AKT-independent pathway essential for PI3K-mediated tumor development and maintenance
AU - Orlacchio, Arturo
AU - Ranieri, Michela
AU - Brave, Martina
AU - Arciuch, Valeria Antico
AU - Forde, Toni
AU - De Martino, Daniela
AU - Anderson, Karen E.
AU - Hawkins, Phillip
AU - Di Cristofano, Antonio
N1 - Funding Information:
We acknowledge the Animal Housing, Histology, shRNA, Analytical Imaging, and Flow Cytometry Core Facilities of Albert Einstein College of Medicine, which are partially supported by the NIH Cancer Center Support Grant to the Albert Einstein Cancer Center (P30CA013330). This work utilized a High-Speed/Resolution Whole Slide Scanner that was purchased with funding from an NIH SIG grant 1S10OD019961-01. The Einstein Shared Facility in Stem Cell Research is supported in part by the ESSCF, NYS-DOH, Contract #C029154A. Research reported in this publication was supported by NIH grants CA172012, CA128943, and CA167839 to A. Di Cristofano.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/12/15
Y1 - 2017/12/15
N2 - Activation of the PI3K–AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.
AB - Activation of the PI3K–AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.
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U2 - 10.1158/0008-5472.CAN-17-2105
DO - 10.1158/0008-5472.CAN-17-2105
M3 - Article
C2 - 29055016
AN - SCOPUS:85038571693
SN - 0008-5472
VL - 77
SP - 6914
EP - 6926
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -
