Searching for a magic bullet in NSCLC: the role of epidermal growth factor receptor mutations and tyrosine kinase inhibitors

The epidermal growth factor receptor (EGFR) has been implicated in the pathophysiology of various cancers, including non-small cell lung cancer (NSCLC). Inhibitors targeting the tyrosine kinase domain of this receptor have been seen to elicit favourable responses in a subset of NSCLC patients. Mutational analysis of the EGFR has revealed that the response to reversible tyrosine kinase inhibitors (TKIs) is a result of the presence of activating mutations present between exons 18 and 21, most frequently the exon 19 deletion and the L858R mutations. After a prolonged treatment with reversible TKIs, patients have been seen to develop resistance that results, in part, from the presence of the secondary T790M mutation in exon 20. Preclinical data suggest that second-generation TKIs may be able to overcome T790M resistance by virtue of their irreversible mode of binding. In addition to the predominant mutations in the EGFR gene, alternative genetic changes between exons 18 and 21 have been observed. Experimental models have demonstrated that TKIs exhibit differential efficacy depending on which mutations are present. Such information may result in the design of highly specific agents that target specific mutations, which could result in more efficacious treatments.