Irreversible Inhibitors of EGFR and Other ErbB Proteins

Returning to the problem of acquired resistance to EGFR TKIs, a number of promising alternative treatments to antagonize EGFR function are receiving some attention in early clinical trials. The predominant and most characterized mechanism of resistance to gefitinib and erlotinib is the presence of the T790M "gatekeeper" mutation in EGFR. Analogous mutations have been identified for other TKI targets that have become resistant to corresponding TKI, such as BCR-Abl, c-Kit and the PDGF receptor, suggesting that these mutations reflect a common problem for the use of the TKI class of targeted therapeutics and may be overcome by a common therapeutic alternative (76,89,90).

Because the T790M mutation affects the ability of reversible TKIs to bind to EGFR, it follows that irreversible inhibitors may circumvent this problem. Irreversible EGFR inhibitors such as HKI-272, HKI-357, and a compound developed by Wyeth Research, EKB-569, have shown some early efficacy (81,91,92). These compounds form cova-lent bonds with the EGFR protein at a distinct cysteine residue C773, within the kinase domain (93,94). The irreversible inhibitors are also able to target C751 of ErbB2, resulting in inhibition of its kinase activity, suggesting that the potency of these compounds may be due to dual inhibition of EGFR and ErbB2.

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