Advances in KRASG12D-targeted therapy: from small-molecule inhibitors to PROTACs and molecular glues.

Abstract

KRAS gene mutations represent one of the most common drivers of human cancers, with particularly high prevalence in pancreatic, lung, and colorectal cancers. Among these, the KRASG12D mutation has long been considered an "undruggable" target because of its unique structural characteristics. This article systematically reviews the biological characteristics and oncogenic mechanisms of the KRASG12D mutation. It highlights its key roles in metabolic reprogramming and shaping the tumor immune microenvironment. The mechanisms by which KRASG12D promotes tumor initiation and progression through activation of downstream signaling pathways such as MAPK/ERK, PI3K/AKT/mTOR, and Ral-GDS are also discussed. The review focuses on various emerging therapeutic strategies targeting KRASG12D. It provides a detailed overview of research advances in small-molecule inhibitors, PROTAC-based approaches, and molecular glue therapies. Finally, the current challenges and opportunities in KRAS inhibitor research are discussed, with the aim of offering new perspectives and strategies for future KRAS-targeted drug discovery.