SGK1 drives resistance to PI3Kα inhibitors in PI3KCA mutant breast cancer.
Major finding: SGK1 drives resistance to PI3Kα inhibitors in PI3KCA mutant breast cancer.
Mechanism: PDK1-bound SGK1 phosphorylates TSC2 to activate mTORC1 signaling in the presence of PI3K blockade.
Impact: PDK1 blockade may sensitize SGK1-expressing PI3KCA mutant tumors to PI3K inhibition.
The PI3K–AKT–mTOR signaling pathway, which regulates critical cellular processes such as proliferation and survival, is frequently dysregulated in many cancers and has been the focus of targeted therapy development. Oncogenic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) activate the PI3K–AKT–mTOR signaling pathway, but patients frequently exhibit intrinsic resistance to PI3K inhibitors. Having recently demonstrated that activated mTORC1 signaling drives the resistance of PI3KCA-mutant breast cancers to PI3K inhibition, Castel and colleagues performed an siRNA screen to identify kinases and/or phosphatases that activate AKT-independent mTORC1 signaling in PI3KCA-mutant breast cancer cells treated with the PI3K inhibitor BYL719. Of the 1,008 kinases and phosphatases targeted in the screen, only knockdown of mTOR and phosphoinositide-dependent kinase 1 (PDK1, encoded by PDPK1) sensitized cells to BYL719 treatment. Consistent with these findings, BYL719 treatment induced the regression of PDK1-depleted xenografts, and combined inhibition of PDK1 and PI3K induced tumor regression. Expression of serum/glucocorticoid regulated kinase 1 (SGK1), which exhibits high identity with AKT in the kinase domain and is a molecular effector of PDK1 signaling, was upregulated in PI3K inhibitor–resistant breast cancer cell lines and tumors, and blockade of SGK1 sensitized PI3K inhibitor–resistant cell lines and xenografts to BYL719 treatment. SGK1 was shown to bind to and phosphorylate the tumor suppressor TSC2, which resulted in the inhibition of TSC2 and subsequently relieved TSC2-mediated repression of mTORC1 signaling. Further, the transcriptional activity and targets of the tumor suppressor forkhead box O3 (FOXO3), which is negatively regulated by SGK1, were upregulated in cells treated with BYL719 and a PDK1 inhibitor. Together, these results identify and characterize the mechanism underlying SGK1-mediated resistance to PI3K inhibitors and identify potential strategies for PI3KCA-mutant targeted therapy design.
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