A new study sheds light on how some small-molecule tyrosine kinase inhibitors, including two that are currently being used clinically to treat cancer, interact with wild-type and mutated forms of the epidermal growth factor receptor (EGFR). The research, published in the March issue of the journal Cancer Cell, published by Cell Press, may help to guide rational use of currently available EGFR inhibitors and provides new direction for the design and development of even more potent inhibitors that are tailored to specific EGFR mutants.
Many human malignancies exhibit mutated forms of the EGFR, a tyrosine kinase that plays a critical role in signaling pathways controlling cell proliferation and survival. Although the specific mechanisms are unclear, studies have shown that some EGFR mutations are associated with increased sensitivity to small-molecule tyrosine kinase inhibitors. To better understand how distinct mutant EGFRs interact with inhibitors on a structural level, Dr. Michael J. Eck from Harvard Medical School and the Dana-Farber Cancer Institute and colleagues studied the enzyme activity of two lung cancer-derived EGFR mutants and determined their crystal structures when bound to several different commonly used inhibitors.
The researchers found that the L858R and G719S EGFR mutants disrupt inhibitory interactions within the EGFR, leading to a characteristic overactivation of the enzyme. Structural examination of the inhibitor complexes, which included the drug gefitinib (Iressa), revealed that the mutations can affect the way the inhibitors interact with the enzyme. Interestingly, the inhibitors gefitinib and AEE788 bind much more tightly to the L858R mutant than to the wild-type EGFR. This finding explains the observation that tumors bearing this mutation have been found to be more responsive to treatment with gefitinib.
The researchers conclude that mutations of the EGFR dramatically influence inhibitor binding and suggest that the different EGFR mutations present distinct targets for application and development of inhibitors. "Although structural divergence in the EGFR mutants may complicate pharmacologic intervention by fragmenting the disease, it may also present an advantage in that it introduces the possibility of developing inhibitors even more potently selective for specific mutants over wild-type EGFR. Inhibitors designed specifically to target mutants such as L858R should, in principle, be less toxic due to reduced inhibition of the wild-type kinase," explains Dr. Eck.
The researchers include Cai-Hong Yun, Yiqun Li, Michele S. Woo, and Michael J. Eck of Harvard Medical School and Dana-Farber Cancer Institute in Boston, MA; Titus J. Boggon of Harvard Medical School and Dana-Farber Cancer Institute in Boston, MA and Yale University in New Haven, CT; Heidi Greulich of Dana-Farber Cancer Institute in Boston, MA and The Broad Institute of Harvard and Massachusetts Institute of Technology in Cambridge, MA; Matthew Meyerson of Harvard Medical School and Dana-Farber Cancer Institute in Boston, MA and The Broad Institute of Harvard and Massachusetts Institute of Technology in Cambridge, MA.
This work was supported in part by NIH grants CA080942 (M.J.E.) and CA116020 (M.M.). M.J.E. is the recipient of a Scholar award from the Leukemia and Lymphoma Society.
Yun et al.: "Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity." Publishing in Cancer Cell 11, 217--227, March 2007. DOI 10.1016/j.ccr.2006.12.017 http://www.cancercell.org
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