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. 2023 Mar 7;29(9):1395–1426. doi: 10.3748/wjg.v29.i9.1395

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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

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Targeted therapies under investigation for the treatment of drug-resistant and metastatic colorectal cancer. Anti-epidermal growth factor receptor, anti-vascular endothelial growth factor/vascular endothelial growth factor receptor, and anti-human epidermal growth factor receptor 2 agents inhibit their respective targets and thus, the downstream effector pathways, PI3K/Akt and RAS/RAF. Other agents directly target and inhibit PI3K, AKT, mammalian target of rapamycin, RAF, mitogen-activated extracellular signal-regulated kinase, or mitogen-activated protein kinases. In addition, anti-hepatocyte growth factor/mesenchymal epithelial transition factor receptor agents target this pathway to inhibit signal transducer and activator of transcription, which is also targeted by Napabucasin. Several novel agents that are aimed at other pathways implicated in colorectal cancer proliferation, survival, resistance, and metastasis are also being evaluated. Targeted pathways include Wnt, Notch, Hedgehog, insulin growth factor/insulin growth factor receptor-1, and transforming growth factor beta. Moreover, immune escape can be hindered through immunotherapy which targets co-inhibitory molecules, mainly programmed death-1/programmed death ligand-1, cytotoxic T lymphocyte-associated antigen 4, and lymphocyte activation gene 3. EFGR: Epidermal growth factor receptor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; HER2: Human epidermal growth factor receptor 2; mTOR: Mammalian target of rapamycin; MEK: Mitogen-activated extracellular signal-regulated kinase; MAPK: Mitogen-activated protein kinases; HGF: Hepatocyte growth factor; MET: Mesenchymal epithelial transition factor receptor; STAT3: Signal transducer and activator of transcription; CRC: Colorectal cancer; IGF: Insulin growth factor; IGF-1R: Insulin growth factor receptor-1; TGF-β: Transforming growth factor beta; PD-1: Programmed death-1; PD-L1: Programmed death ligand-1; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; LAG-3: Lymphocyte activation gene 3; EGF: Epidermal growth factor; TGFβRI/II: Transforming growth factor-Beta type I/II.