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

Abstract

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.

Keywords: Anti-epidermal growth factor receptor targeted therapies; Drug resistance; Metastatic colorectal cancer; Reversal strategies.

Fig. 1

Intrinsic mechanisms of resistance to anti-EGFR mAbs in metastatic colorectal cancer. The intrinsic mechanisms include abnormal activation of oncogenic signalling pathways, aberrant gene expression, metabolic disorders, increased autophagy function and cancer stem cells. For example, genomic alterations and proteic phosphorylation induce activation of the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cascades. ERBB2/MET amplification and abnormal IGF-1R activation stimulate compensatory feedback loop signalling of EGFR. The phenotype shift of cancer stem cells (CSCs) into epithelial-to-mesenchymal transition (EMT) contributes to therapy resistance. Glycolysis, lipid synthesis, fatty acid oxidation and vitamin deficiency in cancer cells also reduced the efficiency of EGFR-targeted therapy. The agents for specific points are also shown in the figure. Abbreviations: CSC, cancer stem cell; EMT, epithelial-to-mesenchymal transition; PI3K, phosphoinositide 3-kinase; IGF-1R, insulin-like growth Factor 1 receptor

Fig. 2

Extrinsic mechanisms of resistance to anti-EGFR mAbs in metastatic colorectal cancer. Tumour microenvironment plasticity confers resistance to EGFR-targeted therapy. Cetuximab and panitumumab suppress tumours through ADCC mediated by NK cells and macrophages. Dysfunction of NK cells and macrophages with lower ADCC impairs the suppression of EGFR-targeted therapy in cancer. Reduced density of effector T cells and increased PD-L1 expression in cancer cells also promote survival from cancer. CAFs promote resistance to targeted therapy by secreting growth factors that activate the RAS or MET pathway. Abnormal angiogenesis always predicts poor response to anti-EGFR mAbs. Therapies focused on the microenvironment are also shown in the figure. Abbreviations: CAFs, cancer-associated fibroblasts; NK cells, natural killer cells; ADCC, antibody-dependent cellular cytotoxicity; PD-1, programmed death 1; PD-L1, programmed death ligand 1. VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor

Fig. 3

Strategies to increase anti-EGFR therapy efficiency in different subtypes of mCRC. Biomarker analysis should be conducted before treatment for mCRC. For patients with disease progression on anti-EGFR therapy, biomarker analysis is still recommended. For mCRC with driver gene alterations, there are some therapies to increase anti-EGFR efficiency. In RAS-mut mCRC, the selected therapies include a combination of RAS inhibitors and anti-EGFR agents, metabolic regulators, immune therapy, cytotoxic drugs and natural bioactive monomers. In RAF-mut mCRC, the main therapy is a BRAF inhibitor. In ERBB2-amp mCRC, ERBB2 inhibitors can be used to promote the antiproliferation of anti-EGFR. In MET-amp mCRC, combined therapy with MET inhibitors and anti-EGFR mAbs was confirmed to be effective. In mCRC with EGFR ECD-mut, new anti-EGFR agents are preferred. In mCRC with no driver gene alteration, multitargeted therapies, metabolic regulators, immune therapy, cytotoxic drugs and antiangiogenic agents can be used with anti-EGFR. Abbreviations: mCRC, metastatic colorectal cancer; EGFR, epidermal growth factor receptor; ERBB2, human epidermal growth factor receptor 2; MET, tyrosine-protein kinase Met; MSI-H, microsatellite instability; dMMR, dysfunctional mismatch repair; PD-1/PD-L1, programmed death-1/programmed death ligand 1; ECD, extracellular domain; WT, wild type; mut, mutation