Jessie Guo, PhD
Targeting Cancer Metabolism to Treat KRAS-driven Lunch Cancer

Metabolic reprogramming is a hallmark of KRAS-driven non-small cell lung cancer (NSCLC), yet the metabolic dependencies imposed by distinct co-occurring mutations remain incompletely understood. Using genetically engineered mouse models and integrated metabolomic approaches, we demonstrated that both tumor-intrinsic and host autophagy support tumor metabolism and promote the progression of KRAS-driven lung cancer. We further identified genotype-specific metabolic vulnerabilities that can be therapeutically exploited. In particular, we found that glucose-6-phosphate dehydrogenase (G6PD) is selectively required for maintaining redox homeostasis and tumor growth in LKB1-deficient (KL), but not TP53-deficient (KP), KRAS-driven lung cancer, revealing a novel therapeutic vulnerability. Finally, our ongoing work has identified methionine synthase (MTR) and folate one-carbon metabolism as critical metabolic dependencies in KP lung tumors. Together, these studies demonstrate how distinct oncogenic genotypes shape metabolic vulnerabilities and provide new opportunities for precision metabolic therapies in KRAS-driven lung cancer.