Abstract 3080: Activation of mTORC2/Akt is amplified during glutamine starvation and is mediated by GCN2

Abstract Highly proliferative cells like cancer cells depend on glucose and glutamine to augment flux through metabolic and biosynthetic pathways. The mechanistic target of rapamycin (mTOR) integrates signals from nutrients and other growth signals to maintain metabolic homeostasis. Whereas mTOR complex 1 (mTORC1) is activated by the presence of nutrients to promote anabolic metabolism, mTORC2 is activated by nutrient fluctuations, leading to increased Akt phosphorylation at Ser473. How mTORC2 signaling can be augmented by nutrient starvation remains poorly understood. Here, we found that General Control Nonderepressible kinase 2 (GCN2), an amino acid starvation-sensing kinase, conveys glutamine depletion to mTORC2. mTORC2 enhances Akt phosphorylation and Akt feeds back to mTORC2 to augment its activity during glutamine starvation. Amino acid starvation in vivo also enhances mTORC2/Akt signaling via GCN2. Our findings reveal that manipulating the GCN2/mTORC2/Akt signaling cassette could have therapeutic benefit to more effectively starve cancer cells. Citation Format: Tatiana Hernandez, Nikhil Patel*, Jedrick Magsino, Jay Kavia, Aparna Ragupathi, Alysta Paneque, Tracy G. Anthony, Guy Werlen, Estela Jacinto. Activation of mTORC2/Akt is amplified during glutamine starvation and is mediated by GCN2 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3080.