Abstract A100: KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC cells

Abstract

Abstract The Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is found in more than 90% of patients with pancreatic ductal adenocarcinomas (PDACs), making it a prime target for therapeutic drug development. HuR (ELAVL1) has been extensively studied in the context of PDAC and also plays a key role in PDAC progression and chemoresistance. In recent years, researchers have shed light on the specific role of the HuR protein in PDAC and its relationship with KRAS signaling. Using in KRASG12D – mutant patient derived models, cell lines derived from GEMM models, and conventional cell lines, we found that HuR CRISPR knock out lines showed more than 80-fold resistance to MRTX1133 (a KRAS inhibitor targeted against G12D mutation) compared to wild type cells. Furthermore, western blot and immunofluorescence studies demonstrated that therapeutic inhibition of KRAS, inhibited HuR protein expression and subcellular localization in as early as 3 hours post-treatment. Furthermore, HuR protein levels decreased post-treatment even under nutrient starvation. Herein, we show that the presence of HuR is necessary for the efficacy of KRAS targeting and Kras inhibition can rapidly degrade HuR protein levels and its active subcellular localization. Mechanistic studies determining the molecular interaction between HuR and KRAS and KRAS related proteins and mRNAs are underway. Taken together with ongoing studies, we are exploring the importance of HuR as a key downstream target of KRAS’ oncogenic activity and if the loss of HuR may be a potent, PDAC therapeutic resistance mechanism. Understanding the interplay between KRAS and HuR could offer a novel strategy to disrupt the oncogenic KRAS signaling cascade and overcome the potential inherent resistance of KRAS-mutant PDACs to promising, KRAS-targeted therapies. Citation Format: Hen Halamish, Michaela Bush, Alexander Smith, Rosalie Sears, Jonathan Brody. KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A100.