Editors' ChoicePharmacology

Targeting the Resistance

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Science Signaling  05 Jan 2010:
Vol. 3, Issue 103, pp. ec1
DOI: 10.1126/scisignal.3103ec1

The discovery of clinically effective inhibitors, such as erlotinib and gefitinib, of the kinase activity of the epidermal growth factor receptor (EGFR) opened new avenues for the treatment of non–small-cell lung cancer (NSCLC) and showed the potential of rational drug design. The most commonly occurring oncogenic mutations increased the affinity for these drugs and decreased the receptor’s affinity for ATP. Unfortunately, some cancers acquire drug resistance through a mutation in the “gatekeeper” residue Thr790 to a Met (T790M). Available inhibitors that are effective against this mutant EGFR also inhibit wild-type EGFR and exhibit dose-limiting toxicity in patients. Thus, Zhou et al. devised a screen for compounds that should irreversibly react with EGFR T790M through the formation of a covalent bond with Cys797. They identified three related pyrimidine compounds, WZ3146, WZ4002, and WZ8040, that inhibited EGFR activity and signaling in gefitinib-sensitive and gefitinib-resistant NSCLC cell lines or in cells engineered to express the T790M mutant form of EGFR but were not toxic in cell lines containing wild-type EGFR. When tested against a panel of 400 kinases, WZ4002 was the most selective for EGFR, and this compound was also the least potent at inhibiting growth of cells with wild-type EGFR. Exposure of cells with activated EGFR mutants to WZ4002 failed to develop the T790M resistance mutation, which suggests that it may be a first-line treatment for NSCLC. Treatment of mouse lung cancer models containing the T790M mutant with WZ4002 resulted in inhibition of phosphorylation of EGFR and downstream targets and increased apoptosis in the mouse lungs and tumor regression. In contrast, WZ4002 did not impair EGFR phosphorylation in mouse hair bulbs, a site of wild-type EGFR activity. Crystallization revealed the structural basis for the selectivity of these compounds and showed that they did form the predicted covalent bond with Cys797 and interacted with the mutant gatekeeper residue. This presents another win for rational drug design.

W. Zhou, D. Ercan, L. Chen, C.-H. Yun, D. Li, M. Capelletti, A. B. Cortot, L. Chirieac, R. E. Iacob, R. Padera. J. R. Engen, K.-K. Wong, M. J. Eck, N. S. Gray, P. A. Jänne, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462, 1070–1074 (2009). [PubMed]