Poster Presentation 30th Lorne Cancer Conference 2018

Interrogating the effects of Keap1 inactivation on the metabolism of Kras-mutant lung adenocarcinomas (#148)

Sheryl Ding 1 2 , S Best 1 2 , B Reljic 3 , ArienaA Kersbergen 1 , Kate Sutherland 1 2
  1. ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute for Medical Research, Parkville, Vic, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, Vic, Australia
  3. Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia

Lung adenocarcinoma (ADC), a subtype of non-small cell lung cancer, is the most common form of lung cancer. Current therapies for KRAS-mutant ADC are limited, and drugs directly targeting KRAS signalling have shown low response rates in patient trials. Loss of function in Kelch-like ECH-associated protein 1 (KEAP1) is found in 18% of KRAS-mutant ADC, and is mutually exclusive with inactivating mutations in Tumour protein 53 (TP53). KEAP1 is an inhibitor of the transcription factor NRF2, which regulates cellular antioxidant and metabolic pathways. Metabolic dysregulation is considered a hallmark of cancer cells, which utilise anaerobic glycolysis and anabolic glucose metabolism in preference to aerobic oxidative phosphorylation in a phenomenon termed the Warburg effect.

We interrogated the consequences of Keap1 loss in KrasG12D-induced ADC using conditional Cre-inducible genetically-engineered mouse models. To identify metabolic vulnerabilities unique to Keap1 inactivation, lung tumours that developed in KrasLSL-G12D/+;p53f/f (Kras/p53) or KrasLSL-G12D/+;Keap1f/f (Kras/Keap1) mice following intranasal delivery of Ad5-CMV-Cre were compared. Gene and protein expression of key enzymes involved in glucose metabolism were measured in spontaneous lung tumours. Glycolytic functional assays were performed in live FACS-isolated tumour cells using a novel protocol.

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 creates a pro-oncogenic metabolic environment to drive lung tumourigenesis. This finding could be key to developing much-needed effective targeted therapies for KRAS-mutant ADC