mTORC2 stabilizes HIF-1β to coordinate metabolic adaptation in lung cancer

Lung tumors often share common signaling dependencies despite significant genetic differences. Researchers have now discovered that the mTORC2 signaling pathway plays a crucial role in the progression of lung cancer. When mTORC2 is overly active in lung adenocarcinoma, it correlates with worse overall survival rates, increased metastasis, and alterations in the tumor's metabolism.

In genetically engineered mouse models with Rictor deletion or overexpression of mTORC2 in Kras-driven lung tumors, the findings confirmed that mTORC2 activity is essential for tumor growth and metabolic adaptation, but not for maintaining normal lung function.

The key mechanism discovered is that mTORC2 stabilizes HIF-1β, which prevents the protein from being broken down by the cell's protein destruction machinery. This stabilization happens through a non-canonical pathway involving PKC-CK2 signaling, separate from the well-known AKT pathway. By examining the overall changes in the tumor's metabolism, the scientists found that sphingolipid metabolism stands out as a particularly promising target for new treatments.

Drugs that block sphingolipid metabolism were shown to slow down the growth of mTORC2-driven lung tumors in the live models.

In summary, this research establishes a new pathway linking mTORC2 signaling in cancer cells to changes in metabolism, highlighting sphingolipid metabolism as a potential therapeutic target for improving outcomes in lung cancer patients.