ABSTRACT The rat sarcoma viral oncogene homolog ( RAS ) family of oncogenes ( KRAS, HRAS , and NRAS ) has long been recognized as among the most frequently mutated driver of human cancer, contributing to approximately one-fifth of all malignancies, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). For nearly four decades, the RAS protein was deemed “undruggable” due to its high-affinity binding to GTP/GDP and its seemingly featureless molecular surface, which lacked traditional small-molecule binding pockets. This challenge was overcome by the discovery of an allosteric binding pocket, the switch-II pocket, specifically on the KRAS G12C mutant protein. This discovery enabled the development and subsequent clinical approval of covalent inhibitors such as sotorasib and adagrasib, marking a milestone in precision oncology. However, the initial success of these agents has been tempered by the rapid emergence of drug resistance, driven by mechanisms including secondary KRAS mutations, compensatory pathway reactivation (e.g., RTK-MAPK feedback loops), and cellular lineage plasticity. This narrative review is based on a structured literature search of major biomedical databases. It chronicles the history of RAS targeting, elucidates mechanisms of acquired resistance, and examines emerging therapeutic strategies aimed at improving long-term outcomes in patients with RAS-driven cancers.
Chinmoy K Bose (Mon,) studied this question.