Research ArticleCancer

Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer

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Science Translational Medicine  18 Dec 2013:
Vol. 5, Issue 216, pp. 216ra177
DOI: 10.1126/scitranslmed.3007205

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A Crystal Clear Cause of Drug Resistance

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used to treat a variety of cancers, including non–small cell lung cancer. EGFR mutations have a wide range of effects on the success of TKI treatment in this cancer type, with some sensitizing the tumors to TKI inhibitors and others making them resistant to targeted therapy. For example, most of the mutations in exon 20, a relatively common mutation site, prevent cancer cells from responding to EGFR inhibitors.

Here, Yasuda and co-workers determined the crystal structure of EGFR with an exon 20 mutation and used a combination of kinetic studies and structural analysis to elucidate the mechanism for these mutants’ differential sensitivity to TKIs. The findings of Yasuda et al. clarify the reasons for the drug resistance of most exon 20 mutations and show the mechanism for the rare mutation in the same exon that increases tumors’ sensitivity to treatment.

In addition to explaining which of the mutants are resistant to targeted inhibition of EGFR and the reasons for this phenomenon, this work could help with the development of future therapeutics. By taking advantage of the crystal structure and detailed insights into the function of mutant EGFR, researchers may be able to design drugs that exploit the unique structural features of resistant mutants and specifically target them for treatment.

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