Decoding RAS Mutations: How KRAS Leads in Pancreatic Malignancies

KRAS has long been considered one of the most significant oncogenic drivers in solid tumors, especially in pancreatic cancer, where it accounts for the vast majority of RAS mutations. Historically labeled as “undruggable,” KRAS and the broader RAS gene family—including NRAS and HRAS—have posed major challenges for targeted therapy development due to the proteins’ structural complexity and lack of obvious binding sites. However, recent advances in molecular oncology are beginning to overturn that notion, leading to renewed interest in targeting these previously elusive mutations.

While KRAS mutations dominate the landscape in pancreatic ductal adenocarcinoma, other RAS family mutations like NRAS and HRAS are present, albeit in smaller subsets of patients. A large-scale analysis of over 27,000 patients demonstrated that more than 90% of RAS mutations were KRAS-based, but a notable minority involved other isoforms. Despite their lower frequency, these non-KRAS mutations still engage the same signaling pathways and present potential therapeutic targets. Their biological relevance reinforces the importance of comprehensive RAS profiling when evaluating patients for targeted therapies.

The growing body of data underscores a broader therapeutic opportunity: designing RAS pathway inhibitors that go beyond the KRAS -centric focus. As more precise molecular diagnostics become standard, clinicians and researchers can begin to define and address these rarer RAS alterations with greater specificity. Though KRAS remains the focal point due to its prevalence and emerging drug options, NRAS and HRAS may follow suit as understanding and technology advance. Altogether, this expansion of focus from “undruggable” to “potentially targetable” opens new doors for personalized treatment strategies across a wider range of patients with RAS-driven cancers.