Recent advances in therapeutic targeting of the KRAS pathway in cancer.

Recent advances in cancer therapy have significantly progressed through targeted inhibition of the rat sarcoma virus (RAS) signalling pathway, particularly focusing on Kirsten rat sarcoma virus (KRAS) mutations prevalent in cancers such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Historically deemed "undruggable," KRAS mutations, especially KRASG12C and KRASG12D, are now effectively targeted by specific inhibitors that have demonstrated promising clinical results. Agents such as Sotorasib, Adagrasib, and Divarasib exhibit notable efficacy against KRASG12C mutations, particularly in NSCLC, with combination strategies significantly improving outcomes, especially in CRC. With over 50 agents currently in development, targeting KRAS has become a rapidly expanding area of cancer therapeutics. However, substantial challenges remain, including optimizing clinical trial designs, particularly in early-phase trials, and integrating pharmacodynamic tools to refine dosing and treatment schedules, thus achieving an optimal balance between efficacy and patient tolerability. This review summarizes recent therapeutic advancements, highlighting the clinical development of KRAS-specific inhibitors, and emphasizes future strategies involving a combination of mutant-specific and broader mutant-independent approaches to overcome resistance, thereby offering promise for more durable cancer control and expanded patient eligibility.