Targeting KRAS in Cancer: Advances in Precision Oncology and Drug Development

KRAS-targeted therapy in oncology: From four decades of failed attempts to a new era of precision medicine

Mutations in the KRAS (Kirsten Rat Sarcoma Viral Proto-oncogene) gene represent among the most prevalent oncogenic drivers in human malignancies, occurring in approximately 25% of all solid tumors. For more than four decades, KRAS was considered pharmacologically intractable due to the protein's picomolar affinity for GTP/GDP and the absence of accessible allosteric binding sites. The identification of the switch-II pocket (S-IIP) and subsequent development of mutation-selective covalent inhibitors targeting the KRAS G12C mutant fundamentally altered this paradigm. Sotorasib and adagrasib, the first approved KRAS G12C inhibitors, have demonstrated meaningful clinical activity in NSCLC and, in combination with anti-EGFR agents, in colorectal cancer. However, both drugs achieve only modest objective response rates of 30–43% in NSCLC with median progression-free survival of approximately six months, substantially below outcomes achieved with targeted therapies directed at EGFR or ALK. Acquired resistance emerges rapidly through on-target KRAS mutations, bypass signaling, and phenotypic plasticity. An expanding pipeline of next-generation agents targeting G12D, G12V, and pan-KRAS approaches offers the first plausible therapeutic options for pancreatic and other KRAS-driven cancers beyond G12C. This narrative review critically evaluates the biological basis of KRAS oncogenesis, the pharmacological obstacles that delayed drug development, the clinical performance and limitations of approved inhibitors, resistance mechanisms and rational combination strategies, and the evidence base and uncertainties surrounding next-generation therapeutic approaches.

KRAS G12C-Targeted Therapy Strategy for Lung Cancer: Mechanism, Clinical Practice and Challenges

This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies.

This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.

From KRAS inhibition to tumor adaptation: mechanistic layers of resistance and therapeutic strategies.

This review synthesizes current knowledge on KRAS resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies.

KRAS-Targeted Therapy in Non–Small Cell Lung Cancer: Current Standards, Resistance Mechanisms, and Emerging Therapeutic Strategies

Direct KRAS inhibition has transformed KRAS G12C–mutated NSCLC from a previously undruggable subtype into a targetable disease, but durable disease control remains an unmet need.

KRAS-Targeted Therapies in NSCLC: Resistance, Combination Strategies, and Emerging Clinical Paradigms