Abstract 5511: KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC

Abstract The Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is found in more than 90% of pancreatic ductal adenocarcinomas (PDACs) making it an attractive therapeutic target. However, even with the recent promise of new KRAS inhibitor drugs, the overall enthusiasm is dampened due to reports of drug resistance. Our recent work has shed light on the critical role of Human Antigen R (HuR), an RNA-binding protein, in its role in KRAS signaling and inhibition. Using KRAS mutant patient derived models and cell lines derived from genetically engineered mouse models, we surprisingly found that transient siRNA silencing or CRISPR gene deletion of HuR, ELAVL1 (HuR-KO) led to resistance of 2.5- fold to more than 1000-fold to KRAS inhibitors compared to control cells. Moreover, other relevant therapies for PDAC such as gemcitabine and Oxaliplatin showed no significant difference between our models. Validating this using an in vivo orthotopic model, MRTX1133 induced profound tumor regression solely in the wild-type group compared to the HuR-KO cohort. The wild-type treated tumors exhibited a 3.8-fold reduction in weight, contrasting with a mere 1.1-fold change observed in the HuR-KO treated group, as compared to the vehicle-treated group (p <0.0001). Using a lipid nanoparticle loaded strategy to deliver HuR mRNA to HuR-KO cells in vitro and in vivo rescued the Kras inhibitor resistance phenotype and made the cells sensitive to a Kras inhibitor. A significant increase in tumor-infiltrating T cells was observed in both wild type and HuR ko treated groups (p < 0.001), however only treated wild-type group had a significant difference in activated (Tbet) CD4+ and CD8+ cells. Moreover, a significant decrease was observed in DCs and an increase in macrophages between vehicle wild-type group to all the other groups, which suggest that the resistance mechanism cannot be completely attributed to the immune microenvironment. Mechanistically, we applied phospho-proteomic, proteomic and RNAseq analysis on our PDAC models treated and untreated with Kras inhibitors which revealed a possible compensation mechanism that occurs with overexpression of IGF family members genes. Furthermore, a potential connection between HuR and MYC has emerged from our data, as MYC is an established HuR target and driver of Kras inhibitor resistance. More mechanistic studies determining the molecular interaction between HuR and KRAS and KRAS related mRNAs are underway. combined with ongoing studies, we highlight a significant breakthrough in the understanding of PDAC cells addiction to Kras signaling in the context of the pro-oncogenic HuR molecule, revealing that the absence of HuR confers resistance to KRAS inhibitor drugs. Understanding the interplay between KRAS and HuR could offer a novel strategy to disrupt the oncogenic KRAS signaling cascade and overcome the potential inherent and acquired resistance mechanisms of KRAS-mutant PDACs to promising, KRAS-targeted therapies. Citation Format: Hen Halamish, Yiefe Guo, Jennifer M. Finan, Vlad Grigoriev, Oleh Taratula, Alexander Smith, Rosalie C. Sears, Jonathan Brody. KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5511.