Glutamine stress promotes metastatic potential via hexosamine biosynthetic pathway activity in KRAS/STK11-mutant lung...

Lung cancer is the leading cause of cancer-related deaths worldwide. Loss of STK11 in KRAS-driven lung adenocarcinoma (LUAD) is observed in approximately 15,000 US lung cancer cases annually and drives an aggressive, resistant disease. STK11 regulates many cellular processes, including metabolism, and loss of this tumor suppressor drives a "glutamine addicted" phenotype that is being considered for targeted therapy. However, recent work from our group revealed the activation of pro-oncogenic signaling in KRAS/STK11-mutant LUAD cells upon glutamine deprivation, suggesting the development of an advantageous adaptation. Here, we demonstrate that STK11 loss in KRAS-driven LUAD cells increases glutamine-dependent mitochondrial respiration, which is metabolically rewired upon exogenous glutamine deprivation to enhance the hexosamine biosynthetic pathway (HBP). Furthermore, our results reveal that enhanced HBP flux in STK11 null KRAS-driven LUAD cells promotes a pro-metastatic phenotype characterized by adherent cell detachment, resistance to apoptosis, and 3D spheroid invasion. This study highlights, for the first time, enhanced HBP flux as a protective shunt in response to glutamine deprivation in KRAS/STK11-mutant LUAD. Our results challenge the potential benefit of glutamine deprivation as a therapeutic intervention in this patient population. Future work aims to further elucidate the role of the HBP in promoting metastasis and to determine the mechanism(s) by which STK11 null KRAS-driven LUAD cells upregulate the HBP.