High-frequency KRAS mutations in pancreatic adenocarcinoma: prognostic significance and potential co-targeting therapies.

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is among the most frequently mutated oncogenes across multiple cancers. Developing prognostic indicators based on KRAS mutations and advancing targeted KRAS inhibitors remain critical challenges in oncology. Notably, different KRAS mutations are associated with distinct biological behaviors, each carrying unique prognostic and therapeutic implications. The study aims to investigate and explore the characteristics of KRAS mutations and their impact on cancer patient prognosis.

Methods: We performed a comprehensive pan-cancer analysis using publicly available The Cancer Genome Atlas (TCGA) Program data to investigate the prognostic significance of KRAS mutations in pancreatic adenocarcinoma (PAAD), colorectal cancer (CRC), and lung adenocarcinoma (LUAD). Kaplan-Meier survival analysis and univariate and multivariate Cox regression models were applied to assess the impact of KRAS mutations on patient outcomes. Additionally, KRAS mutations were detected using Sanger sequencing in genomic DNA extracted from paraffin-embedded tissues of patients enrolled from 2022 to 2024. Mutation rates and their associations with genetic background factors were analyzed.

Results: The pan-cancer analysis revealed high KRAS mutation frequencies in PAAD (77.4%), COADREAD (41.1%), and LUAD (27.2%), with the most prevalent mutations being G12C, G12D, and G12V. Sanger sequencing further confirmed the high mutation frequencies of KRAS^{G12C, G12D, G12V} in PAAD (54/129), CRC (28/40), and LUAD (24/35). Patients harboring KRAS^{G12C, G12D, G12V} mutations in PAAD exhibited significantly reduced overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS), while no significant survival differences were observed in CRC and LUAD. Multivariate Cox regression identified KRAS^{G12C, G12D, G12V} as independent prognostic risk factors in PAAD. Moreover, we predict that gefitinib, afatinib, erlotinib, and selumetinib could serve as potential co-targeting therapies for KRAS mutations.

Conclusions: KRAS mutations serve as independent prognostic risk factors in PAAD, and targeting these mutations may offer a promising therapeutic approach to improve patient outcomes.