Proteomic Perspectives on KRAS-Driven Cancers and Emerging Therapeutic Approaches

KRAS mutations are implicated in approximately 23% of all human malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma (PDAC) (~92%), colorectal cancer (CRC) (~49%), and non-small cell lung cancer (NSCLC) (~35%). The recent approval of the KRAS^G12C-specific inhibitors for NSCLC represents a pivotal advancement in KRAS-targeted therapy. Nevertheless, the emergence of intrinsic and acquired resistance to KRAS-targeted therapies poses a significant clinical obstacle to targeting KRAS, which necessitates a deeper understanding of the resistance mechanisms. Recent progress in proteomic studies has enabled comprehensive profiling of the proteomic alterations driven by KRAS mutations, offering valuable insights into the disrupted KRAS interactome, aberrant signaling pathways and dysregulated cellular processes contributing to tumorigenesis. This review discusses current knowledge on proteomic alterations associated with oncogenic KRAS mutations, with particular focus on allele-specific proteome signatures and the roles of post-translational modifications (PTMs) of KRAS in modulating the functional networks. Furthermore, we highlight recent therapeutic advances targeting KRAS variants and discuss emerging resistance mechanisms from a proteomics-informed perspective.