Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies KRAS mutations are prevalent in pancreatic ductal adenocarcinomas (PDAC), with 90–92% of cases harboring mutations in the oncogene KRAS. These mutations trigger canonical MAPK signaling, making KRAS a key target in precision oncology. However, the structure of the altered KRAS protein, lacking a binding pocket and high affinity for GTP, has hindered drug development. The emergence of covalent KRAS G12C inhibitors has renewed interest in targeting KRAS. Despite this, early resistance and the dense stromal niche of PDAC complicate treatment. Understanding the pleiotropic effects of KRAS is crucial for progress in this disease. KRAS is a member of the RAS oncogene family, with three isoforms: KRAS, NRAS, and HRAS. KRAS mutations occur at hotspots, with G12D, G12V, and G12R being the most common in PDAC. These mutations increase KRAS-GTP affinity and inhibit GAP-mediated hydrolysis, contributing to resistance. KRAS amplification is also associated with aggressive PDAC phenotypes. KRAS mutations often occur alongside inactivating mutations in tumor suppressor genes such as TP53, CDKN2A, and SMAD4. These co-mutations contribute to the heterogeneity of KRAS mutated PDAC and influence survival. KRAS and progression to invasive PDAC are linked to precursor lesions such as PanIN and IPMNs. KRAS mutations influence the tumor microenvironment (TME), promoting immunosuppression and creating a favorable environment for tumor growth. KRAS mutations also impact metabolism, driving aerobic glycolysis and altering nutrient scavenging pathways. Targeting KRAS has been a focus of research, with direct G12C inhibitors such as sotorasib and adagrasib showing promise in clinical trials. However, resistance mechanisms, including secondary mutations and bypass pathways, limit the effectiveness of these inhibitors. Non-G12C inhibitors, such as MRTX1133, are being developed for other KRAS mutations prevalent in PDAC. Pan-RAS inhibitors, such as RMC-6236, are also under investigation. Combination strategies with upstream and downstream inhibitors, immunotherapy, and other agents are being explored to overcome resistance and improve outcomes. SHP2 and SOS1 inhibitors are being tested for their potential to enhance KRAS targeting. Adoptive cell therapy and cancer vaccines are also being investigated as potential strategies. Despite these advances, challenges remain in overcoming resistance and defining optimal combination strategies for KRAS mutated PDAC. The future of KRAS targeting in PDAC will likely involve personalized approaches based on KRAS allelic status and a deeper understanding of the tumor microenvironment and metabolic needs of individual patients.Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies KRAS mutations are prevalent in pancreatic ductal adenocarcinomas (PDAC), with 90–92% of cases harboring mutations in the oncogene KRAS. These mutations trigger canonical MAPK signaling, making KRAS a key target in precision oncology. However, the structure of the altered KRAS protein, lacking a binding pocket and high affinity for GTP, has hindered drug development. The emergence of covalent KRAS G12C inhibitors has renewed interest in targeting KRAS. Despite this, early resistance and the dense stromal niche of PDAC complicate treatment. Understanding the pleiotropic effects of KRAS is crucial for progress in this disease. KRAS is a member of the RAS oncogene family, with three isoforms: KRAS, NRAS, and HRAS. KRAS mutations occur at hotspots, with G12D, G12V, and G12R being the most common in PDAC. These mutations increase KRAS-GTP affinity and inhibit GAP-mediated hydrolysis, contributing to resistance. KRAS amplification is also associated with aggressive PDAC phenotypes. KRAS mutations often occur alongside inactivating mutations in tumor suppressor genes such as TP53, CDKN2A, and SMAD4. These co-mutations contribute to the heterogeneity of KRAS mutated PDAC and influence survival. KRAS and progression to invasive PDAC are linked to precursor lesions such as PanIN and IPMNs. KRAS mutations influence the tumor microenvironment (TME), promoting immunosuppression and creating a favorable environment for tumor growth. KRAS mutations also impact metabolism, driving aerobic glycolysis and altering nutrient scavenging pathways. Targeting KRAS has been a focus of research, with direct G12C inhibitors such as sotorasib and adagrasib showing promise in clinical trials. However, resistance mechanisms, including secondary mutations and bypass pathways, limit the effectiveness of these inhibitors. Non-G12C inhibitors, such as MRTX1133, are being developed for other KRAS mutations prevalent in PDAC. Pan-RAS inhibitors, such as RMC-6236, are also under investigation. Combination strategies with upstream and downstream inhibitors, immunotherapy, and other agents are being explored to overcome resistance and improve outcomes. SHP2 and SOS1 inhibitors are being tested for their potential to enhance KRAS targeting. Adoptive cell therapy and cancer vaccines are also being investigated as potential strategies. Despite these advances, challenges remain in overcoming resistance and defining optimal combination strategies for KRAS mutated PDAC. The future of KRAS targeting in PDAC will likely involve personalized approaches based on KRAS allelic status and a deeper understanding of the tumor microenvironment and metabolic needs of individual patients.