More than half of patients with stage III lung cancer were theoretically not eligible for concurrent chemoradiation. Less toxic alternatives are needed for these patients.

First-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG-PET is the best predictive test for PFS.

Background: The most frequently altered gene in lung adenocarcinoma (ADC) is the KRAS oncogene. There are currently no effective treatments to target KRAS-mutant ADC. Loss of function in Kelch-like ECH-associated protein 1 (KEAP1) is co-mutated in 18% of KRASmutant ADC and is mutually exclusive with inactivating mutations in Tumour protein 53 (TP53). KEAP1 is a negative regulator of the transcription factor NRF2, which regulates cellular antioxidant and metabolic pathways. Metabolic dysregulation is considered a hallmark of cancer cells, which utilize anaerobic glycolysis and anabolic glucose metabolism in preference to aerobic oxidative phosphorylation in a phenomenon termed the Warburg effect. Method: We interrogated the consequences of Keap1 loss in Kras G12D -induced ADC using conditional genetically engineered mouse models (GEMMs). To examine metabolic features unique to Keap1-mutant ADC, GEMMs with Kras LSL-G12D/+ alone or with either the p53 flox/flox allele (Kras/p53) or Keap1 flox/flox allele (Kras/Keap1) were investigated. Gene and protein expression of key enzymes involved in glucose metabolism were measured in spontaneous lung tumors. Glycolytic functional assays were performed in live FACS-isolated tumor cells using a novel protocol. Result: Major alterations in glycolytic function were identified as unique features of Keap1 inactivation in lung adenocarcinomas carrying oncogenic activation of Kras. Loss of Keap1 function in Kras-mutant ADC therefore created a pro-oncogenic metabolic environment to drive lung tumourigenesis. Conclusion: Targeting metabolic dependency in KRASmutant tumors may provide a unique method of treating this aggressive subset of lung ADC.