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. 2021 Oct 4;20:128. doi: 10.1186/s12943-021-01422-7

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 3 — Indirect KRAS suppression strategy. The activation of receptor tyrosine kinases, such as members of the epidermal growth factor receptor (EGFR) family, activate KRAS through the growth factor receptor-bound protein 2 (GRB2)-SH2–containing protein tyrosine phosphatase 2 (SHP2)-SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) pathway. The mutant KRAS protein accumulates in the guanosine triphosphate (GTP)-bound state, leading to the activation of downstream effector pathways, especially the RAF-MEK-extracellular signal regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) pathways. The localization of KRAS on the cell membrane is the first step in subsequent KRAS activation, which is mediated by enzymes, including but not limited to farnesyltransferase (FT), geranylgeranyltransferase 1 (GGT1), and isoprenylcysteine carboxyl methyltransferase (ICMT). In addition to directly inhibiting KRAS (exemplified by covalent allele-specific inhibitors that bind to KRAS-G12C), multiple approaches can indirectly inhibit the oncogenic pathway of KRAS by targeting upstream regulators, downstream effectors, and KRAS expression and processing. The main drugs or reagents used for indirect KRAS inhibition are shown in red (for clinical trials or approved for use in patients) or green (for preclinical research)