Lung Cancer and KRAS -Its Molecular Biology/Genetics and Therapeutic Strategy-

Takamasa Koga, Tetsuya Mitsudomi
2022 Haigan  
━━ Kirsten rat sarcoma viral oncogene homolog (KRAS) is a frequently activated oncogene in human cancer. Since its discovery over 30 years ago, efforts to develop therapies targeting KRAS have been unsuccessful. KRAS has been considered an undruggable target for several reasons: difficulty designing molecules that compete with the guanosine triphosphate (GTP) binding site because of the very high affinity between KRAS and GTP, and redundancy in post-transcriptional modifications required for
more » ... brane association and downstream signaling pathways. Inhibition of a single signaling pathway or post-transcriptional modification leads to the activation of other pathways. In addition, the patient survival of cancers with KRAS mutations is not always dependent on KRAS. However, a small molecule that covalently binds cysteine of the G12C mutant form of KRAS and that locks KRAS in its guanosine diphosphate (GDP)-bound inactive state was reported in 2013. Since then, several companies have developed KRAS G12C -specific small-molecule inhibitors, such as sotorasib and adagrasib. The United States Food and Drug Administration granted accelerated approval to sotorasib in 2021 as a second-line and subsequent therapy for non-small-cell lung cancer (NSCLC) harboring a KRAS G12C mutation. Further research, including the development of direct inhibitors targeting sites other than G12C in KRAS, combination strategies with KRAS G12C inhibitors, countermeasures after resistance acquisition, and biomarkers for effective patient selection, are awaited.
doi:10.2482/haigan.62.188 fatcat:l3c7ojaoyrftllhhdusfvcavfe