{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:52:22Z","timestamp":1787727142391,"version":"build-2784847793"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal solid malignancies, with limited therapeutic progress despite decades of cytotoxic chemotherapy. About 90% of PDAC tumors harbor activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS), making oncogenic KRAS signaling a longstanding therapeutic target. Although KRAS G12C inhibitors have demonstrated clinical success in lung and colorectal cancers, this strategy has not translated to the same degree in the glycine-to-arginine substitution at codon 12 (G12R), present in 15%-20% of PDAC tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A focused narrative review of the literature was conducted using PubMed and Google Scholar to examine structural, biochemical, and clinical data relevant to KRAS G12R, binding pocket dynamics, therapeutic outcomes, and novel approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>G12R substitution introduces a bulky, positively charged arginine side chain that sterically occludes the binding pocket of KRAS (Switch II pocket), precluding both covalent and competitive inhibitor engagement. In addition to structural inaccessibility, G12R mutations exhibit distinct signaling rewiring, including impaired phosphoinositide 3-kinase alpha (PI3K\u03b1) and mitogen-activated protein kinase (MEK) interactions, along with increased survival driven by amplified autophagy. These features limit the efficacy of pocket-directed inhibitors and downstream MEK blockade. Emerging pan-RAS(ON) ternary complex inhibitors bypass the occluded pocket by recruiting cyclophilin A to block effector signaling and may provide an effective means to address KRAS G12R-mutated disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>KRAS G12R defines a structurally and biologically distinct subset of PDAC characterized by binding-pocket occlusion and increased survival pathways. Effective treatment will require pocket-independent strategies or targeting of G12R-specific biological vulnerabilities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag155","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T11:50:12Z","timestamp":1780055412000},"source":"Crossref","is-referenced-by-count":2,"title":["KRAS G12R in pancreatic cancer: why this mutation resists current inhibitor strategies"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8125-1727","authenticated-orcid":false,"given":"Kenneth A","family":"Kern","sequence":"first","affiliation":[{"name":"Affiliate Faculty, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , San Diego, CA 92109,","place":["United 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