Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and
cancer cell growth.
Polyamine metabolism is frequently dysregulated and considered a therapeutic target in
cancer. However, targeting
polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of
polyamine catabolism promotes
glutamine metabolism, leading to a targetable vulnerability in
lung cancer. Genetic and pharmacological activation of
spermidine/
spermine N1-acetyltransferase 1 (SAT1), the rate-limiting
enzyme of
polyamine catabolism, enhances the conversion of
glutamine to
glutamate and subsequent
glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support
lung cancer cell proliferation and survival. Simultaneous
glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of
glutamine transport,
glutaminase, or GSH biosynthesis in combination with activation of
polyamine catabolism synergistically suppresses
lung cancer cell growth and xenograft
tumor formation. Together, this study unveils a previously unappreciated functional interconnection between
polyamine catabolism and
glutamine metabolism and establishes cotargeting strategies as potential
therapeutics in
lung cancer.