Current and Future Targeted Therapies for Non-small-cell Lung Cancers With Aberrant EGF Receptors

Shanthi Kanthala; Sandeep Pallerla; Seetharama Jois


Future Oncol. 2015;11(5):865-878. 

In This Article

EGFR Gene Mutations

In 2003, EGFR TKIs were first administered to nonselected patients with advanced NSCLC, but only very few patients showed dramatic response.[31] Subsequent studies revealed that a subset of patients who showed dramatic response to EGFR TKIs was found to harbor gene mutations in the intracellular tyrosine kinase domain that mediates downstream signaling of the EGFR. The mutations exist in exons 18–21 which correspond to N-lobe and part of C-lobe of EGFR kinase domain. The most frequently found EGFR mutations in patients with NSCLC include short in-frame deletions in exon 19 and a specific point mutation in exon 21 at 858; these constitute 80–90% of the mutations detected.[31] In previous studies, NSCLC patients showing effective response to gefitinib were found to have mutations primarily in exons 18, 19 and 21. Most of these activating mutations exist near the ATP binding cleft of EGFR. These mutated EGFRs show lower affinity to ATP compared with the wild-type EGFR. The presence of deletion mutations in EGFR exon 19 in patients receiving gefitinib or erlotinib therapy increased their median survival time by 38 months; in patients with L858R mutation in exon 21, survival time was improved by 17 months.[32] Other less commonly occurring mutations include point mutations in exon 18 (G719C, G719S and G719A) (Figure 1) and exon 20 (V765A and T783A).[15] On the contrary, mutations in exon 20 are associated with resistance to TKIs such as erlotinib and gefitinib. These mutations could be in-frame duplication and/or insertion, and could also be point mutations. EGFR exon 20 insertion mutations are typically located near the C-helix of the tyrosine kinase domain and only account for up to 4% of all EGFR mutations. Preclinical models have shown that the most prevalent EGFR exon 20 insertion mutated proteins are resistant to gefitinib and erlotinib. Exon 20 mutations were observed in small number of patients and had a shorter duration of gefitinib response than those with other mutations. The significance of this resistance by mutations on exon 20 is not well established. Further studies are needed for a better outcome of treatment of lung cancer patients with EGFR exon 20 mutations.[33,34]

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.

ADC histology, female gender, nonsmoking history and Asian ethnicity were the clinical predictors for harboring EGFR-activating mutations, and patients with these show promising response to EGFR TKIs.[31] As a result of the investigation, mutations in exons 18, 19 and 21 are now the most reliable predictive biomarkers for the efficacy of EGFR TKIs. At present, patients are tested for EGFR mutations, and it is proposed that those testing positive should receive EGFR TKIs as initial therapy for metastatic lung cancer. Subsequently, erlotinib has been approved by the FDA as the first-line treatment for the patients with metastatic NSCLC harboring mutations in the EGFR in exon 19 and a specific point mutation in exon 21.

After 9–24 months, patients treated with gefitinib or erlotinib will develop resistance[35] due to the secondary mutations in exon 20, which is a substitution of a hydrophilic threonine residue (T) for a bulkier and hydrophobic methionine (M) in codon 790 (T790M) (Figure 1).[36] Recently, the FDA approved afatinib, an irreversible TKI that is active against EGFR mutations targeted by first-generation TKIs like erlotinib or gefitinib and also against those not sensitive to these standard therapies. About 50% of acquired resistance in ADC cases was associated with T790M. Initially, it was thought that T790M would prevent binding of EGFR TKIs to the ATP cleft of EGFR, but later, based on crystal structure analysis, it was discovered that T790M mutation restores the ATP binding capability of mutated EGFR. Based on these results, it can be suggested that T790M is the best predictive biomarker for acquired resistance of EGFR TKIs. In addition to T790M, insertion mutations in exon 19 and exon 20 also cause acquired resistance to EGFR-TKIs.