Advances in biomarkers of resistance to KRAS mutation-targeted inhibitors

KRAS mutations represent the most common driver genetic alterations in multiple malignant tumors, particularly exerting well-defined oncogenic driver roles in non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. The recent success of KRAS G12C mutation-specific allosteric inhibitors marks a therapeutic milestone in KRAS-targeted oncology. However, the rapid emergence of drug resistance in clinical applications has significantly limited the durable efficacy of these agents. The resistance mechanisms exhibit profound complexity, encompassing multidimensional pathways such as secondary/co-occurring mutations, compensatory reprogramming of signaling pathways, cellular lineage plasticity, and immune evasion within the tumor microenvironment. Studies have demonstrated that the identification of resistance-associated biomarkers is not only of critical clinical value for predicting treatment response and early warning of resistance but also provides a key entry point for dissecting resistance mechanisms. This review systematically summarizes the latest research advances in KRAS-mutant inhibitor resistance biomarkers, with a focus on the analysis of resistance molecular mechanisms, discovery of predictive biomarkers, current limitations and challenges, and exploration of biomarker-based combination therapy strategies. By integrating basic research and clinical data, we highlight the breakthroughs required to realize the application value of resistance biomarkers and prospects future research directions and priorities, aiming to provide a biomarker-related theoretical framework for precision therapy of KRAS-mutant tumors and accelerate the clinical translation of resistance-overcoming strategies.