TMIC-102. The glioma kinomic landscape is altered among mice with diverse gut microbiomes

BACKGROUND It has been previously shown in mouse models of glioma that the gut microbiota can influence response to immunotherapy as well as the immune activation in glioma tumors. We hypothesize that changes in the gut microbiota and subsequent immune activation would impact the intrinsic tumor signaling pathways. In this study, we sought to determine if variations in the gut microbiome of mice would impact the global tumor kinase activity in an orthotopic murine model of glioma. METHODS Mice with different gut microbiomes (HuM1, HuM2, and MuM) were injected intracranially with GL261 glioma tumors. HuM1 and HuM2 are human donor microbiota transplants, while MuM is a murine microbiota control. At moribund, mice were euthanized and tumors dissected, and flash frozen for kinomic analysis. Equal protein concentrations were used on the PamChip arrays (PTK -tyrosine kinome; STK -serine/threonine kinome) for kinase profiling and 16s rRNA sequencing was used to determine microbiome differences. RESULTS Each microbiome line was significantly different with regards to taxonomic diversity, alpha diversity, and beta diversity. Regarding predicted kinase activity within the tumors, there was significant overlap in upstream identified kinases that were altered by tumor compared to naïve brains. Specifically, all mice (HuM1, HuM2, and MuM) had tumor induced increased activation of Src and Fyn kinases and inhibition of PKA-alpha compared to naïve brain controls. However, there were differences, specifically in HuM1, that exhibited decreased FLT1, EPHA4, Fer, IKK-alpha, CK1-delta and other kinase activity. Additionally, HuM2 tumors had fewer significant changes in kinase activity overall compared to HuM1 and MuM kinase profiles. CONCLUSIONS Overall, we found that there were different kinase activation profiles in the tumors among the mice with the different gut microbiomes. Further evaluation will determine if targeting of specific kinases would be therapeutically beneficial based on the composition of the gut microbiome.