KRAS alterations are a hallmark of pancreatic ductal adenocarcinoma (PDAC) found in >90% of tumors. This review examines the historical evolution of the understanding of RAS and its central role in PDAC biology. We summarize the various downstream effectors, feedback loops, and resistance mechanisms that play a pivotal role in PDAC oncogenesis. Our review explores the early development of covalent inhibitors of KRAS G12C and efforts at specific inhibition of other codons and newer approaches of targeted protein degradation. We subsequently summarize the development of panRAS inhibitors and allosteric and switch-region targeting before focusing on rational therapeutic blockade of crosstalk and upstream signaling, with attention to synthetic lethality approaches transitioning from preclinical to early-phase in-human clinical trials. This review elaborates on ongoing KRAS-specific siRNA research and evolving KRAS-directed immunotherapies. We conclude by outlining the current KRAS clinical trial landscape and future areas of investigation.

Background: Biliary tract cancers (BTCs) carry a poor prognosis driven by frequent diagnosis at advanced or metastatic stages. Inadequate tissue sampling impedes biomarker-directed selection of therapy that could potentially improve outcomes over limited chemotherapeutic options. Plasma cell-free DNA (cfDNA) yields limited sensitivity. However, given its direct contact with the tumor, bile holds promise as a locally enriched source of tumor-derived cfDNA for evaluation. Methods: Following the PRISMA-ScR guidelines, we searched PubMed/MEDLINE and EMBASE without date restrictions. Seventeen primary studies of bile cfDNA in cholangiocarcinoma (CCA), gallbladder carcinoma (GBC), pancreatic ductal adenocarcinoma (PDAC), and primary sclerosing cholangitis (PSC) were synthesized narratively. Results: Compared to plasma cfDNA, Bile cfDNA was isolated at higher concentrations and in longer fragments than plasma cfDNA; bile cfDNA demonstrated higher concordance with matched tumor tissue, capturing more actionable alterations. Pairing it with serum CA19-9 or newer bile-derived markers improved performance. Emerging data suggest a role in early detection of CCA during PSC surveillance. Conclusions: Bile cfDNA as a liquid biopsy medium offers analytic advantages over plasma for detecting and profiling biliary malignancy. Standardized collection, extraction, and reporting protocols and prospective multicenter validation are needed before routine use.