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 mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in
tumors. Approximately 20% of KRAS-mutant LUAD
tumors carry loss-of-function mutations in the KEAP1 gene encoding
Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), 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. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in
lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant
cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of
glutaminase. Finally, we provide a rationale for stratification of human patients with
lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung
tumors as likely to respond to
glutaminase inhibition.