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Sheryl Ding



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    MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
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      MA24.10 - Interrogating the Metabolic Effects of Keap1 Inactivation in Adenocarcinoma (ID 13764)

      11:35 - 11:40  |  Author(s): Sheryl Ding

      • Abstract
      • Presentation
      • Slides

      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 KRAS-mutant 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.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We interrogated the consequences of Keap1 loss in KrasG12D-induced ADC using conditional genetically engineered mouse models (GEMMs). To examine metabolic features unique to Keap1-mutant ADC, GEMMs with KrasLSL-G12D/+ alone or with either the p53flox/flox allele (Kras/p53) or Keap1flox/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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Targeting metabolic dependency in KRAS-mutant tumors may provide a unique method of treating this aggressive subset of lung ADC.

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