Zhang, JoshuaDarman, LilyHassan, Md SazzadVon Holzen, UrsAwasthi, Niranjan2024-03-262024-03-262023Zhang J, Darman L, Hassan MS, Von Holzen U, Awasthi N. Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review). Oncol Rep. 2023;50(5):206. doi:10.3892/or.2023.8643https://hdl.handle.net/1805/39511Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in solid tumors. More than 90% of pancreatic ductal adenocarcinoma (PDAC) are driven by mutations in the KRAS gene, suggesting the importance of targeting this oncogene in PDAC. Initial efforts to target KRAS have been unsuccessful due to its small size, high affinity for guanosine triphosphate/guanosine diphosphate, and lack of distinct drug‑binding pockets. Therefore, much of the focus has been directed at inhibiting the activation of major signaling pathways downstream of KRAS, most notably the PI3K/AKT and RAF/MAPK pathways, using tyrosine kinase inhibitors and monoclonal antibodies. While preclinical studies showed promising results, clinical data using the inhibitors alone and in combination with other standard therapies have shown limited practicality, largely due to the lack of efficacy and dose‑limiting toxicities. Recent therapeutic approaches for KRAS‑driven tumors focus on mutation‑specific drugs such as selective KRASG12C inhibitors and son of sevenless 1 pan‑KRAS inhibitors. While KRASG12C inhibitors showed great promise against patients with non‑small cell lung cancer (NSCLC) harboring KRASG12C mutations, they were not efficacious in PDAC largely because the major KRAS mutant isoforms in PDAC are G12D, G12V, and G12R. As a result, KRASG12D and pan‑KRAS inhibitors are currently under investigation as potential therapeutic options for PDAC. The present review summarized the importance of KRAS oncogenic signaling, challenges in its targeting, and preclinical and clinical targeted agents including recent direct KRAS inhibitors for blocking KRAS signaling in PDAC.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalPancreatic cancerNon-small-cell lung carcinomaPancreatic ductal carcinomaLung neoplasmsPancreatic neoplasmsArticle