Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies

• Published in: Journal of experimental & clinical cancer research Vol. 40; no. 1; pp. 328 - 17
• Main Authors: Zhou, Jing, Ji, Qing, Li, Qi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.10.2021; BioMed Central; BMC
• Subjects: Analysis; Animals; Anti-epidermal growth factor receptor targeted therapies; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Cancer therapies; Care and treatment; Cell growth; Clinical Decision-Making; Clinical Trials as Topic; Colorectal cancer; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - etiology; Colorectal Neoplasms - metabolism; Cytotoxicity; Development and progression; Disease Management; Drug Development; Drug resistance; Drug Resistance, Neoplasm - drug effects; Efficiency; Energy Metabolism - drug effects; Epidermal growth factor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Feedback; Gene Amplification; Gene mutations; Genetic aspects; Health aspects; Humans; Insulin-like growth factors; Kinases; Ligands; Medical prognosis; Melanoma; Metabolism; Metastasis; Metastatic colorectal cancer; Microsatellite Instability; Molecular Targeted Therapy - adverse effects; Molecular Targeted Therapy - methods; Monoclonal antibodies; Mutation; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - etiology; Neovascularization, Pathologic - metabolism; Phosphorylation; Protein Binding; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Reversal strategies; Review; Signal Transduction - drug effects; Treatment Outcome; Tumor Microenvironment - drug effects; Tumors; Vascular endothelial growth factor; Reversal strategies; Anti-epidermal growth factor receptor targeted therapies; Drug resistance; Metastatic colorectal cancer
• DOI: 10.1186/s13046-021-02130-2
• ISSN: 1756-9966; 0392-9078

Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). Cetuximab can prolong survival by 8.2 months in RAS wild-type (WT) mCRC patients. Unfortunately, resistance to targeted therapy impairs clinical use and efficiency. The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. Multiple therapeutic strategies have been investigated extensively to overcome resistance to anti-EGFR mAbs. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. For intrinsic mechanisms, therapies mainly cover the following: new EGFR-targeted inhibitors, a combination of multitargeted inhibitors, and metabolic regulators. In addition, new cytotoxic drugs and small molecule compounds increase the efficiency of cetuximab. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis. The directions include the modification or activation of immune cells and suppression of CAFs and anti-VEGFR agents. In this review, we focus on the mechanisms of resistance to anti-EGFR monoclonal antibodies (anti-EGFR mAbs) and discuss diverse approaches to reverse resistance to this therapy in hopes of identifying more mCRC treatment possibilities.