Understanding KRAS: mechanisms of resistance and future therapeutic strategies

Mutations in oncogenes are key drivers of human malignancies, with the Kirsten rat sarcoma viral oncogene homolog (KRAS) representing one of the most frequently altered and clinically significant oncogene mutations, highly prevalent, contributing to tumor initiation, progression, and therapeutic resistance. This systematic literature review explores KRAS from its structure, function, mutations, and molecular characteristics to mechanisms of resistance and emerging therapeutic strategies. KRAS encodes a small guanosine-5′-triphosphate (GTPase) transducer protein that acts as a molecular switch, alternating between an active (GTP-bound) and inactive guanosine diphosphate (GDP-bound) state under the regulation of guanine nucleotide exchange factors (GEFs). Oncogenic mutations impair intrinsic GTPase activity, locking KRAS in a constitutively active GTP-bound form that persistently triggers major oncogenic pathways, thereby enhancing cell proliferation, promoting survival, and conferring resistance. Resistance further develops through secondary mutations, bypass signaling, and underscores the biomechanical complexity of KRAS-driven oncogenesis. This perception shifted with the development of glycine-to-cysteine (G12C) specific inhibitors, which demonstrated clinical benefit and response in subsets of patients. This response faded over time, with strong resistance emerging. Ongoing advances in structure-based drug design, molecular modeling, immunotherapy, and PROTAC-based degradation with delivery systems as nanoparticles or RNA-guided platforms are now redefining the future therapeutic landscape. Furthermore, a deeper molecular and mechanistic understanding of KRAS-associated resistance will guide the next generation of precision strategies, with the ultimate goal of transforming KRAS-driven cancers from refractory to potentially curable diseases.