Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. 
Our lab utilizes the power of CRISPR/Cas9-somatic genome editing in a mouse model of Kras-driven LUAD to examine the effects of Keap1 loss in lung cancer progression to show that loss of Keap1 hyper-activates Nrf2 and promotes Kras-driven LUAD. We are currently combining CRISPR/Cas9-based genetic screening and in vivo somatic genome editing to elucidating genotype specific vulnerabilities in Keap1-mutant tumors. Our goal is to characterize synthetic lethal interactions that specifically ablate cells or tumors that have a hyper activated Nrf2 response.