Current and future targeted therapies for non-small-cell lung cancers with aberrant EGF receptors

Abstract

Expression of the EGF receptors (EGFRs) is abnormally high in many types of cancer, including 25% of lung cancers. Successful treatments target mutations in the EGFR tyrosine kinase domain with EGFR tyrosine kinase inhibitors (TKIs). However, almost all patients develop resistance to this treatment, and acquired resistance to first-generation TKI has prompted the clinical development of a second generation of EGFR TKI. Because of the development of resistance to treatment of TKIs, there is a need to collect genomic information about EGFR levels in non-small-cell lung cancer patients. Herein, we focus on current molecular targets that have therapies available as well as other targets for which therapies will be available in the near future.

Keywords: EGF receptor; acquired resistance; afatinib; cetuximab; gefitinib; neratinib; predictive markers; trastuzumab; tyrosine kinase inhibitors.

Figure 1. Crystal structures of wild-type and mutant EGF receptor kinase domain showing the ATP binding site occupied by the anticancer drug gefitinib

Note the mutations G719S and L858R near the binding site shown as blue sticks. The kinase domain of EGF receptor and its mutants are shown in overlapped ribbons: green – wild-type (PDB ID 2ITY), gefitinib is shown as red sticks; yellow – mutant (PDB ID 2ITO), gefitinib is shown as orange sticks; and cyan – mutant (PDB ID 2ITZ), gefitinib is shown as magenta sticks. These mutations affect the binding of the drug to the receptor and cause resistance to cancer treatment. Mutation in the binding site that restores the ATP binding (T790M) is also shown in blue. T790M was suggested to be used as a biomarker for acquired resistance of tyrosine kinase inhibitor therapy.

Figure 2. Protein–protein interaction inhibition method for the development of drugs for different types of EGF receptor-overexpressed cancer

The extracellular domains of EGFR and HER2 are shown as heterodimers. Note that domain IV is involved in the interaction of two proteins. Domain IV can be targeted with small molecules, peptides or peptidomimetics for the inhibition of dimerization. The region of PPI and its inhibition is marked by an oval shape. The model of EGFR:HER2 heterodimer was generated [108,109] using the crystal structures of EGFR (PDB ID 3NJP) [110] and HER2 (PDB ID) [111] with a homodimer of EGFR as a template (PDB ID 3NJP). EGFR: EGF receptor; PPI: Protein–protein interaction.