Oral Presentation 33rd Lorne Cancer Conference 2021

Targeting altered metabolism in the treatment of kras-mutant lung adenocarcinoma (#16)

Sarah A Best 1 2 , Ariena Kersbergen 2 , Dovile Anderson 3 , Darren Creek 3 , Kate Sutherland 1 2
  1. Medical Biology, Melbourne University, Melbourne, Victoria, Australia
  2. Cancer Biology And Stem Cells, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  3. Proteomics and Metabolomics Facility, Monash Institute of Pharmaceutical Sciences, Melbourne, Victoria, Australia

The tumour microenvironment (TME) contains a rich source of nutrients that sustain tumour cell growth and propel tumour progression. The availability of glucose and glutamine in the TME are also essential in the development and activation of effector T cells that have the potential to exert anti-tumour function. Recently, the inhibition of glutaminase, the enzyme that converts imported glutamine to glutamate, has garnered interest with the hypothesis that glutaminase inhibition would both decrease tumour metabolism and growth, while increasing available glutamine in the TME for use by effector T cells. KRAS-mutant lung adenocarcinoma (ADC) cell lines with co-mutation in KEAP1 and STK11/Lkb1 have displayed significant glutamine dependency in preliminary studies, highlighting the potential utility of glutaminase inhibition in this tumour type.

 

To investigate the metabolism and immune microenvironment of KRAS-mutant ADC, we generated a cohort of conditional genetically engineered mouse models (GEMMs) that reflect the key subtypes of patient KRAS-mutant ADC. GEMMs with KrasLSL-G12D/+ alone or carrying a p53flox/flox allele (Kras/p53), Keap1flox/flox allele (Kras/Keap1) and/or Lkb1flox/flox allele (Kras/Lkb1; Kras/Keap1/Lkb1) were investigated. Key features of tumour development, immune microenvironment and metabolism were investigated in the spontaneous lung tumours.

 

We found that, while Kras/Keap1 tumours have an increased glycolytic rate and usage of the Pentose Phosphate Pathway (PPP) compared to Kras/p53 tumours; loss of Lkb1 was key to increased glutamine dependency. Increased glutamine in the tumour was associated with the phenotypic activation of CD8+ T cells in response to anti-PD1 checkpoint immunotherapy. The spontaneous GEMMs were next used to investigate metabolic treatment modalities. Surprisingly, glutaminase inhibition resulted in negative consequences to the CD8+ T cell response. Nevertheless, robust tumour control was achieved using the PPP inhibitor 6-aminonicotinamide (6-AN) in Kras/Keap1 GEMMs and human cell line xenograft models, suggesting metabolic inhibition is a viable approach in KEAP1-mutant ADC.