Abstract A027: HuR drives immune evasion, metastases and KRAS addiction in pancreatic ductal adenocarcinoma: implications for IO-based and KRAS inhibitor therapies

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest diseases, with a 5-year survival rate of only 13%. While rare mutations have been identified to drive PDAC therapy resistance, undiscovered potent, post-transcriptional regulatory mechanisms could be key to understanding this resistance. The RNA-binding protein HuR (ELAVL1) is known to play a critical role in PDAC oncogenesis by stabilizing mRNA transcripts involved in key oncogenic pathways. Our lab has shown that HuR is overexpressed in PDAC tumor and promotes multiple pro-survival signaling pathways. To study HuR-mediated PDAC progression in immune competent models that reflect the tumor microenvironment, we deleted ELAVL1 via CRISPR-Cas9 in Kras-p53 mutant-driven (KPC) murine PDAC cells and found that HuR-knockout (KO) KPC tumors grew more slowly compared to KPC wild-type (WT) tumors in orthotopic implantation settings. Using flow cytometry and multiplex immunohistochemistry, we found that HuR-WT tumors had significantly less T cell infiltration and greater endothelial cell infiltration compared to HuR-KO tumors. Deep transcriptomic and proteomic profiling revealed that HuR mediates the expression of multiple metabolic pathways and determines mRNA and protein cargo loading in secreted extracellular vesicles (EVs). In fact, when mice bearing HuR-KO tumors were injected with purified EVs from HuR-WT cells, both tumor size and endothelial cell function in leukocyte trafficking were rescued. In the context of T cell function, HuR directly enriched transcripts in the mTOR pathway, and inhibition of mTOR activity in HuR-WT tumor cells rescued T cell function in co-culture. Consistent with these observations linking tumor-intrinsic HuR to dysregulated endothelial and anti-tumor immune function, HuR-KO tumors were significantly more responsive to immune checkpoint blockade therapy as compared to WT-HuR tumors. Similarly, in a Kras-MYC driven mouse model, HuR-WT tumor cells metastasized at significantly higher rates to the liver compared to HuR-KO tumors. Finally, given the recent advancements in KRAS inhibitors, we tested their efficacy in these pre-clinical models, and surprisingly, we observed that HuR-KO tumors were up to >100-fold more resistant to KRAS inhibition than WT tumors. These observations could be explained by HuR expression and activity being closely linked to aberrant KRAS signaling, where loss of HuR leads to the reliance of compensatory pathways and drives PDAC cells away from a KRAS addiction phenotype, thus providing a setting of KRAS inhibitor resistance. Accordingly, surviving PDAC cells post-KRAS inhibitor treatment in vivo lost HuR expression compared to untreated tumors. Together, these findings highlight that HuR is a global post-transcriptional regulator that: 1) reshapes the tumor microenvironment to be immune evasive; 2) is involved in a feed-forward loop enhancing KRAS pathway activation; and 3) facilitates PDAC metastatic potential. Strategies to target HuR activity and use it as a potential biomarker could lead to improved therapeutic outcomes. Citation Format: Miffy Guo, Jennifer Finan, Hen Halamish, Katherine Pelz, Robert Eil, Rosalie Sears, Jonathan Brody. HuR drives immune evasion, metastases and KRAS addiction in pancreatic ductal adenocarcinoma: implications for IO-based and KRAS inhibitor therapies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A027.