Year: 2026
Type: preprint
Abstract: 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 uncover HIF-1β as a selective metabolic effector downstream of mTORC2 that promotes lung tumor progression. 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 identified extensive metabolic rewiring downstream of the mTORC2-HIF-1β axis, with sphingolipid metabolism emerging as a prominent and therapeutically exploitable vulnerability. Accordingly, pharmacological targeting of sphingolipid metabolism markedly impaired the growth of mTORC2-driven lung tumors in vivo . Together, our findings establish a non-canonical mTORC2-HIF-1β signaling axis that couples oncogenic signaling to metabolic adaptation and defines therapeutically actionable metabolic vulnerabilities in lung cancer.
Authors: Morgane Paque, Ning An, Marine Leclercq, Anisa Aliju, Elodie Renaude, Domien Vanneste, Denis Heusdens, Jair Marques Junior, Chinmayi Pednekar, Tillmann Bedau, Juan Fernández-García, Fabienne Perin, Raphaël Vanleyssem, Christian Seca, Kim Eiden, Patrick Roncarati, Engy Shokry, Rachel L. Baird, Leah Officer-Jones, Silvia Martinelli, Ian Powley, David Sumpton, Thomas Marichal, Didier Cataldo, Emmanuel di Valentin, Steven Goosens, Geert Berx, John Le Quesne, Michael Herfs, Johannes Meiser, Reinhard Büttner, Mélanie Planque, Johannes V. Swinnen, Sarah-Maria Fendt, Alex von Kriegsheim, Pierre Close, Arnaud Blomme
Institutions: University of Liège, Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, University Hospital Cologne, VIB-KU Leuven Center for Cancer Biology, KU Leuven, Luxembourg Institute of Health, Cancer Research UK Scotland Institute, Walloon Excellence in Lifesciences and Biotechnology, Ghent University, Cancer Research Institute Ghent
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7207520870