Abstract IA06: Oncogenic Ras control of the tumor immune microenvironment

摘要: Despite RAS proteins being exceptionally well-validated cancer targets, little progress has been made towards targeting them effectively in the clinic. We have optimized combination of effector pathways downstream for specific activity on KRAS mutant cells, with combinations MEK, IGF-1R and mTORC1 highly effective preclinical models. Replacing MEK G12C inhibitor reduces toxicity combination. However, these are not able to eradicate tumors, which recur once treatment is stopped. In order improve effectiveness RAS-targeted therapies, we investigated mechanisms whereby signaling can promote local immune suppression tumor microenvironment through inducing expression checkpoint proteins, suppressive cytokines, extracellular enzymes. One such pathway involves control mRNA stability PD-L1 multiple cytokines by 3′AU rich element binding protein, tristetraprolin. Another that appears be strongly upregulated tumors adenosine, immunosuppressive. test potential targeted therapies immunotherapies resulting from studies, developed new mouse models lung show more realistic interaction system tumor, seen existing genetically engineered used study due their lack heterogeneity mutational burden. This work also detailed analysis using imaging mass cytometry comparison between manipulatable human clinical samples TRACERx study. Citation Format: Julian Downward. Oncogenic Ras [abstract]. In: Proceedings AACR Special Conference Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA06.