Targeting Heme Metabolism for the Treatment of KRAS- KEAP1-Mutant Lung Adenocarcinoma

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Project Abstract KRAS-driven lung adenocarcinoma (LUAD) represents a major non-small cell lung cancer (NSCLC) genetic subtype for which treatment options remain limited. Mutations in the KEAP1/NRF2 signaling pathway are common events in several solid cancers, including KRAS-driven LUAD, and are associated with poor patient prognosis and outcomes. KEAP1 loss of function (LOF) triggers stabilization of the transcription factor NRF2 which leads to dramatic metabolic and antioxidant reprogramming that confers proliferative and survival advantages to tumor cells. However, these selective advantages also confer targetable metabolic dependencies which arise specifically in the context of KEAP1/NRF2 mutations. The enrichment of these mutations in LUAD carrying undefined or untargetable driver mutations makes unmasking therapeutic vulnerabilities particularly urgent. Identifying metabolic liabilities within KRAS-mutant LUAD would enable the application of precision medicine for the improvement of patient outcomes. In this proposal, I present findings which suggest Keap1-mutant tumors show increased sensitivity to disruption of heme synthesis and that this phenotype is due to Nrf2 activation. I outline my proposed approach to interrogate the metabolic and genetic underpinnings of this apparent vulnerability. I then describe how I will assess if this pathway shows potential for targeted therapy in preclinical models of Kras-driven LUAD including the use of genetically engineered mouse models of LUAD. Hypomorphic mutations in nearly all heme synthesis enzymes have been reported to cause some form hereditary hepatic porphyria. Despite the potential severity of these diseases, their existence among the general population, including healthy adults, provides evidence for the existence of a therapeutic window for heme synthesis inhibition for the treatment of cancer. This fellowship application aims to uncover a novel metabolic target in this genetic subtype of LUAD and will yield a better understanding of a fundamental, yet understudied, metabolic pathway in the development of lung cancer.