Targeting mutated KRAS in the first‐line therapy

KRAS is one of the most frequently mutated oncogenes in cancer. 1 Codon 12, 13 and 61 mutations are frequently observed as the hot spot mutations in various cancers.Normally, KRAS protein functions as a molecular switch downstream of cell surface receptors, such as epidermal growth factor receptor (EGFR), plateletderived growth factor receptor, etc., shuttling GTP-bound active state and GDP-bound inactive state, which turns on and off the growth factors' signals that activate MAPK, PI3K/AKT/mTOR and other signalling pathways fundamental for cell proliferation, differentiation and survival.The oncogenic mutations lock the KRAS at the active state, resulting in contributing to tumorigenesis.Genetically engineered mouse models containing tissue-specific Kras codon 12 mutation have developed clinically relevant cancers in the corresponding tissues, which indicates the central driver role of KRAS mutation in cancer formation and progression. 2herefore, targeting the mutated KRAS is considered an ideal therapeutic strategy in the KRAS-mutated cancers.Especially, KRAS codon 12 mutation is detected in 90% of pancreatic cancer, 1 which suggests the tumour addiction to the mutated KRAS in the most deadly cancer with a 5year survival of still around 10%.However, KRAS has been undruggable for more than 40 years, because of its relatively smooth protein structure and lack of approachable binding pocket. 1 Recently, KRAS G12C-specific covalent inhibitors, sotorasib and adagrasib, that lock KRAS to a GDP-bound inactive state, were developed and clinically approved for the treatment of cancers with KRAS G12C mutation, 3,4 with significant therapeutic efficacy, especially in non-