Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge for clinical oncology. Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function mutations in KEAP1, a negative regulator of NRF2, which is the master transcriptional regulator of the endogenous antioxidant response. Using CRISPR/Cas9-based somatic editing in a genetically engineered mouse model of KRAS-driven LUAD we demonstrated that loss of Keap1 hyper- activates Nrf2 and dramatically accelerates KRAS-driven LUAD. Combining CRISPR/Cas9- based genetic screening and metabolic analyses, we showed that Keap1 mutant cells are dependent on increased glutamine metabolism, and this property can be therapeutically exploited through the pharmacological inhibition. In this application we focus on characterizing the molecular mechanisms and therapeutic potential of targeting glutamine metabolism in KRAS- driven KEAP1 mutant LUAD, and other cancers with hyperactivation of the NRF2 antioxidant pathway. This application aims to: 1) Assess the therapeutic potential of inhibiting glutamine utilization in both human and murine KRAS-driven LUAD models with KEAP1 mutations, 2) Characterize the metabolic mechanisms underlying glutamine dependency in KEAP1 mutant LUAD, and 3) Determine the therapeutic potential of inhibiting glutaminolysis in cancers with hyperactivation of the NRF2 pathway. Our studies will provide a rationale for sub-stratification of patients with hyperactivation of the NRF2 pathway as treatment responders to glutaminase inhibitors, which is pertinent to the goals of precision medicine. !
KRAS-driven non-small cell lung cancer (NSCLC) remains one of the most aggressive and lethal solid tumors, therapeutic options and outcomes for NSCLC have remained virtually unchanged over the past thirty years. Using novel CRISPR/Cas9-based genome-engineering technologies we have established a unique and rapid research program to functionally characterize lung cancer mutations and identify genotype-specific metabolic vulnerabilities that can lead to novel therapeutic approaches in KRAS-driven lung cancer.
| Sayin, Volkan I; LeBoeuf, Sarah E; Singh, Simranjit X et al. (2017) Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife 6: |
| Alvarez, Samantha W; Sviderskiy, Vladislav O; Terzi, Erdem M et al. (2017) NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551:639-643 |
| Romero, Rodrigo; Sayin, Volkan I; Davidson, Shawn M et al. (2017) Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med 23:1362-1368 |
