Unlocking drug sensitivity in KRAS

Since the KRAS proto-oncogene was first identified in 1982, KRAS has long been regarded as an “undruggable” target. KRAS 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 KRASG12C 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.