mTORC2-HIF-1β signaling creates a targetable sphingolipid vulnerability in lung cancer [Polysome-seq]

Despite extensive genetic heterogeneity, lung tumors frequently converge on shared signaling dependencies that remain therapeutically underexploited. Here, we identify mTORC2 signaling as a convergent dependency across genetically distinct lung cancer subtypes and demonstrate that RICTOR-dependent mTORC2 activity promotes tumor progression through HIF-1β-dependent sphingolipid reprogramming. Elevated mTORC2 signaling in lung adenocarcinoma was associated with poor overall survival, metastatic dissemination and metabolic rewiring. Using complementary genetically engineered mouse models of Rictor deletion or overexpression in Kras-driven lung tumors, we show that mTORC2 activity is dispensable for normal lung homeostasis but required for tumor progression and metabolic adaptation in vivo. Mechanistically, mTORC2 stabilized HIF-1β by preventing its ubiquitin-independent proteasomal degradation through a non-canonical PKCα-CK2 signaling axis, independently of AKT. Integrated multi-omics analyses revealed that mTORC2-HIF-1β signaling drives extensive sphingolipid remodeling through the regulation of key metabolic enzymes, including SPHK1 and SPTLC2. Accordingly, pharmacological inhibition of sphingolipid metabolism markedly impaired the growth of mTORC2-driven lung tumors in vivo. Together, our findings uncover a previously unrecognized mTORC2-HIF-1β-sphingolipid signaling axis that creates targetable metabolic vulnerabilities in lung cancer.