Novel approaches to target KEAP1 mutant tumors

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. Loss of KEAP1 hyper-activates NRF2 and dramatically accelerates KRAS-driven LUAD. Furthermore, LUAD patients with KEAP1 mutations do not respond to standard-of-care, including the recently approved KrasG12C inhibitors, making this one of the most aggressive and hard to treat solid tumors. Building on our prior studies, we have observed that KEAP1 mutant cells have an altered metabolism that can be therapeutically targeted. In this application we focus on characterizing the molecular mechanisms and therapeutic potential of targeting the polyol and fructolysis pathways by both genetic and pharmacological approaches in multiple KRAS-driven KEAP1 mutant LUAD pre-clinical models. In addition, using newly established models of KrasG12C-mutant LUAD with KEAP1 mutations we will determine the therapeutic potential of standard of care KrasG12C inhibitor Sotorasib in combination with a KHK inhibitor that blocks fructolysis. Ultimately, our studies will provide a rationale for inhibiting the fructolysis in KEAP1 mutant LUAD and support the sub-stratification of patients with hyperactivation of the NRF2 pathway as treatment responders to therapies targeting the polyol and fructolysis pathways, which is pertinent to the goals of precision medicine.