The Molecular Basis for Sensitivity ofEGFR Mutants to Selective TKIs

A central and as yet poorly understood concept in the arena of gefitinib and erlotinib pharmacology is the cellular and biochemical basis for sensitivity to these inhibitors. Early functional analyses of the mutant receptors in cell-based kinase assays had suggested they exhibit an approximately ten-fold increased sensitivity to inhibition by gefi-tinib relative to wild-type EGFR (45,55).

Recent in vitro biochemical analyses utilizing purified isolated mutant EGFR kinase domains have verified these results, suggesting that the mutant EGFRs exhibit a higher Km (binding constant) for ATP and an increased affinity for the TKIs, or a lower K value, than wild-type EGFR (56). Does this hypersensitivity ofEGFR mutants to inhibition by gefitinib and erlotinib really correspond to an increased affinity for these compounds? The question has raised some controversy.

Another study in which a novel phage-display methodology was employed to calculate Kd values for various kinase inhibitors with 113 different kinases found that the ratios of Kd for gefitinib and erlotinib between mutant and wild-type EGFR proteins were not significantly greater than 3 or less than 0.33 (57). The limitation of these analyses was that the assay was performed by competition with immobilized staurosporine rather than ATP. Thus, the biochemical basis for the hypersensitivity of EGFR mutants to inhibition by gefitinib and erlotinib remains to be fully elucidated.

Recent studies that have attempted to identify biomarkers for sensitivity to EGFR TKIs, have revealed some interesting results. Firstly, it appears that the up-regulation of ErbB3 is seen in a significant proportion of gefitinib-sensitive cell lines, which has been suggested to be a mechanism allowing for the coupling ofEGFR to the PI3 K-AKT signaling pathway, resulting in EGFR-dependent survival signaling (58,59). Secondly, it has been suggested that cells that have undergone epithelial to mesenchymal transition (EMT), are inherently resistant to gefitinib (60,61).

EMT is a process that occurs during normal development and during tissue home-ostasis, which essentially involves a transdifferentiation mechanism allowing epithelial cells to migrate from attached substrata to distal sites within tissues. EMT occurs as a result of down-regulation of epithelial markers such as E-cadherin and up-regulation of mesenchymal proteins such as vimentin. The process is thought to contribute to the malignancy of tumor cells, allowing them to invade into the vasculature and subsequently metastasize. The molecular basis for resistance to gefitinib in cells that have undergone EMT remains to be fully elucidated, although the expression level of E-cadherin seems to be one determinant (61).

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