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

J Exp Clin Cancer Res. 2021 Oct 18;40(1):328. doi: 10.1186/s13046-021-02130-2.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Clinical Decision-Making
  • Clinical Trials as Topic
  • Colorectal Neoplasms / diagnosis
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / metabolism
  • Disease Management
  • Drug Development
  • Drug Resistance, Neoplasm / drug effects*
  • Energy Metabolism / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Amplification
  • Humans
  • Ligands
  • Microsatellite Instability
  • Molecular Targeted Therapy / adverse effects
  • Molecular Targeted Therapy / methods
  • Mutation
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / metabolism
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction / drug effects
  • Treatment Outcome
  • Tumor Microenvironment / drug effects


  • Antineoplastic Agents
  • Ligands
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors