Unlocking drug sensitivity in KRAS

<p indent="0mm">Since the <italic>KRAS</italic> proto-oncogene was first identified in 1982, KRAS has long been regarded as an “undruggable” target. <italic>KRAS</italic> mutations frequently occur in highly lethal solid tumors such as pancreatic cancer, colorectal cancer, and lung cancer, representing a key driver in tumor progression; thus, KRAS was coined “the beating heart of cancer”. Wild-type KRAS relies on growth factors for activation and GTP hydrolysis accelerated by GAPs for inactivation. Oncogenic KRAS proteins are GAP-insensitive, resulting in prolonged activation that excessively stimulates downstream pathways, drives tumor initiation and progression, and consequently makes KRAS a major focus of precision therapy research. Recently, breakthroughs in structural biology and medicinal chemistry have propelled the development of innovative KRAS-targeted drugs. The transformative success of KRAS^G12C covalent inhibitors has profoundly reshaped the landscape of targeted cancer therapy. This review summarizes the evolution of KRAS-targeted drug strategies, outlines the structural design and mechanisms of inhibitors, discusses challenges related to drug resistance, and prospects new precision treatment strategies targeting KRAS.