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. 2022 Aug 26;19(10):637–655. doi: 10.1038/s41571-022-00671-9

Fig. 1. The RAS signalling pathway and therapeutic approaches to target this pathway in cancer.

Fig. 1

Numerous direct inhibitors have been developed to target mutant RAS proteins, either in their inactive, GDP-bound state (‘KRAS-off inhibitors’) or in their active, GTP-bound state (‘RAS-on inhibitors’). Many of these inhibitors are being evaluated in clinical trials. The RAS signalling pathway has many upstream and downstream mediators, which are attractive targets for combination therapies with RAS inhibitors to improve antitumour responses and to mitigate intrinsic and acquired resistance; agents that have been combined with direct KRAS inhibitors in preclinical or clinical studies are listed. Therapeutic cancer vaccines against mutant RAS epitopes and small interfering RNA (siRNA)-based approaches that target oncogenic RAS isoforms are also under ongoing development. ILK, integrin-linked kinase; mTORC2, mTOR complex 2; PI3K, phosphatidylinositol 3-kinase; RTK, receptor tyrosine kinase.