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Identification of Gpd2 and Scl1a5 as Therapeutic Targets in Lung Cancers with Mutations in the Oxidative Stress Pathway
Massachusetts Institute of Technology
Small molecule
Oncology
Target Identification or Validation
• GDP inhibitor regulates NFR2/KEAP1 pathway by inhibiting glutaminase in KRAS-mutant lung adenocarcinoma (LUAD).
• This technology uses glutaminase inhibition as a therapy for KEAP1/NRF2 dysregulated NSCLC.
• These inventors identified that mutation of SLC1A5 or GPD2 in combination with KEAP1/NRF2 dysregulation leads to synthetic lethality. This finding led to the observation that KEAP1/NRF2 dysregulation results in dependence on glutamine metabolism and suggested that inhibition of glutamine metabolism may be a therapeutic target for KEAP1/NRF2 dysregulated NSCLC.
• In proof-of-concept experiments, the inventors demonstrated that inhibition of glutaminase, a key enzyme in glutamine metabolism, with the small molecule CB-893 led to significantly increased lifespan and decreased tumor burden in both mouse and human patientderived-xenograft in vivo models.
• Glutaminase inhibition is an attractive therapeutic target for KEAP1/NRF2 dysregulated NSCLC, and that KEAP1/NRF2 dysregulation could be used as a theragnostic marker to direct NSCLC therapy.
US20210361603A1
Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nature Medicine. (2017)
