Tuesday, May 7, 2024
5/7/2024
PROJECT SUMMARY/ABSTRACT 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 This application aims to: 1) Assess the therapeutic potential of novel glutamine antagonist in both human and murine KRASG12D- and KRASG12C-driven KEAP1 mutant LUAD pre-clinical models, 2) Provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2 mutant tumors as likely responders to glutamine antagonists and determine the therapeutic potential of combining with clinically relevant KC-Is with DRP-104. 3) Characterize the metabolic mechanisms underlying glutamine antagonist sensitivity in KRAS-driven KEAP1 mutant LUAD, and 4) Identify mechanisms of resistance to glutamine dependence. Our studies will provide a rationale for sub-stratification of patients with hyperactivation of the NRF2 pathway as treatment responders to DRP-104, a novel glutamine antagonist in clinical trials, which is pertinent to the goals of precision medicine.
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