Comprehensive review of targeted therapy for colorectal cancer

Abstract

Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.

Fig. 1. United States of America Food and Drug Administration (FDA)-approved targeted agents in colorectal cancer.

VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; EGFR: epidermal growth factor receptor

Fig. 2. Pathways offering potential sites for targeted therapy.

CRC: colorectal cancer; VEGF/VEGFR: vascular endothelial growth factor/vascular endothelial growth factor receptor; EGF/EGFR: epidermal growth factor/epidermal growth factor receptor; HGF: hepatocyte growth factor; c-MET: mesenchymal–epithelial transition factor; IGF/IGF-1R: insulin-like growth factor/ insulin-like growth factor 1 receptor; TGF: transforming growth factor

Fig. 3. Overview of National Comprehensive Cancer Network (NCCN)-recommended targeted agents.

HGF: hepatocyte growth factor; c-MET: mesenchymal–epithelial transition factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; EGFR: epidermal growth factor receptor; EGF: epidermal growth factor; HER2: human epidermal growth factor 2; CTLA-4: cytotoxic T lymphocyte-associated antigen 4; PD-1: programmed death-1; PD-L1: programmed death ligand 1; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B, also known as PKB; mTOR: mammalian target of rapamycin; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase. *These agents have not been recommended by the NCCN. **This agent has been approved by the National Medical Products Administration of China (NMPA), but not by the United States of America Food and Drug Administration (FDA)

Fig. 4. National Comprehensive Cancer Network (NCCN)-recommended strategy for metastatic colorectal cancer targeted therapy.

mCRC: metastatic colorectal cancer; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor; PD-1/L1: programmed death-1/programmed death ligand 1; dMMR: deficient mismatch repair; pMMR: proficient mismatch repair; HER2: human epidermal growth factor 2; BSC: best supportive care; WT: wild type; mut: mutated; amp: amplified. *The NCCN recommends initial administration of PD-1/PD-L1 therapy only in patients in poor functional status

Fig. 5. Crosstalk and bypass mechanisms between pathways.

VEGFR: vascular endothelial growth factor receptor; EGFR: epidermal growth factor receptor; c-MET: mesenchymal–epithelial transition factor; IGF-1R: insulin-like growth factor 1 receptor; TGF-β: transforming growth factor-β; RON-R: recepteur d’Origine nantais; PDGFR: platelet-derived growth factor receptor; *with multiple isoforms