Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer

• Published in: Molecular oncology Vol. 6; no. 1; pp. 15 - 26
• Main Authors: Dienstmann, Rodrigo, De Dosso, Sara, Felip, Enriqueta, Tabernero, Josep
• Format: Journal Article
• Language: English
• Published: United States Elsevier B.V 01.02.2012; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: Biomarker; Cancer therapies; Clinical trials; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Drug development; Drug Discovery - methods; Drug Resistance, Neoplasm - drug effects; Epidermal growth factor; Epidermal growth factor receptor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - immunology; ErbB Receptors - metabolism; Humans; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Monoclonal antibodies; Monoclonal antibody; Mutation; Non-small cell lung carcinoma; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Resistance; Review; Reviews; Tumors; Tyrosine kinase inhibitor; Vascular endothelial growth factor; RR; Biomarker; NSCLC; OS; Tyrosine kinase inhibitor; EGF; HGF; VEGF; Monoclonal antibody; FGFR; Epidermal growth factor receptor; EGFR; Resistance; TKI; PI3K; TGF-α; mAbs; mTOR; VEGFR; IGF-1R; PFS; ADCC; MET
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2011.11.009

Epidermal growth factor receptor (EGFR) is a validated target in different human malignancies. EGFR tyrosine kinase inhibitors (TKIs) are known to contribute considerably to the extension of progression-free survival in EGFR-mutant non-small cell lung cancer and monoclonal antibodies (mAbs) targeting EGFR have also improved the efficacy outcomes in KRAS wild-type colorectal cancer. Nevertheless, a significant percentage of lung and colorectal cancer patients do not respond to anti-EGFR agents and secondary resistance after initial benefit is a challenging reality faced by clinicians. Extensive preclinical work on the potential mechanisms of resistance to EGFR inhibitors in different disease settings has guided the development of second-generation irreversible EGFR TKIs, more efficient anti-EGFR mAbs, and combination strategies with agents targeting other receptors and downstream effectors. In order to elucidate the role of the multiple therapeutic strategies under investigation to overcome EGFR inhibitors-resistance, rational drug development based on stringent preclinical data, biomarker validation and proper selection of patients in the ongoing clinical trials are of paramount importance. Preliminary results of clinical trials evaluating these approaches will be discussed in this manuscript, with emphasis on TKIs in lung cancer and mAbs in advanced colorectal cancer. CRC: colorectal cancer; EGFR: epidermal growth factor receptor; TKI: tyrosine kinase inhibitor; mAb: monoclonal antibody; IGF-1R: insulin-like growth factor 1 receptor; MET: mesenchymal–epithelial transition receptor; NSCLC: non-small cell lung cancer. [Display omitted] ► KRAS and secondary EGFR mutations confer resistance to EGFR inhibitors. ► Upregulation of parallel signaling pathways is a frequent adoptive response. ► Irreversible EGFR TKIs may overtake resistance in lung cancer. ► More efficient anti-EGFR mAbs are promising agents in colorectal cancer. ► Combination of targeted agents is a straightforward approach under investigation.