Lung Cancer-derived EGFR Mutants

A new study sheds light on how some small-molecule tyrosine Kinase inhibitors, including two currently used clinically for treating cancer, interact with wild and mutated forms of epidermal growth factor receptor (EGFR). Research, reported in the latest issue of the journal Cancer Cell, published by Cell Press, can help to guide the rational use of currently available EGFR inhibitors and give new direction for design and development of even more potent inhibitors that are tailored to specific EGFR mutants.

A number of human diseases have mutated forms of EGFR tyrosine Kinase, which play a vital role in signalling pathways control cell proliferation and survival.Eventhough the specific mechanisms are unclear, studies have shown that certain EGFR mutations are associated with increased susceptibility to small-molecule tyrosine Kinase inhibitors; to better understand how different mutant EGFRs interact with inhibitors on a structural level, Dr. Michael j. Eck from Harvard Medical School and Dana-Farber as well as ballet Cancer Institute and his colleagues studied the enzyme activity in two lung cancer-derived EGFR mutants and discovered its crystal structures when bound to a variety of commonly used inhibitors.

The researchers found that the L858R and G719S EGFR mutants disrupt inhibiting interactions within the EGFR, which results in a characteristic overactivation of this enzyme.Structural study of inhibitor complexes, which covered the drug gefitinib (Iressa), showed that the mutations can affect how inhibitors interacts with the enzyme. Inhibitors gefitinib and AEE788 bind interesting, much closer to L858R mutant than wild. EGFRThis explains the observation that tumors carry this mutation has been found to be more responsive to gefitinib therapy.

The researchers note that mutations in EGFR drastically affect inhibitor binding and suggests that the various EGFR mutations present clear targets for application and development of inhibitors. "Eventhough structural abnormalities of the EGFR mutants can complicate the dosage regimens intervention of fragmentation disease, it can also be an advantage in that it enables them to develop even more potently selective inhibitors for specific mutants of wild. EGFRInhibitors designed specifically to target the mutants that L858R should in principle be less toxic due to reduced inhibition of wild China, "explains Dr. Eck.

Researchers, inter alia, Cai-Hong Yun, Yiqun Li, Michele p. Woo and Michael j. Eck Harvard Medical School and Dana-Farber as well as ballet Cancer Institute in Boston, Massachusetts, Titus j. Boggon from Harvard Medical School and Dana-Farber as well as ballet Cancer Institute in Boston, MA and Yale University in New Haven, CT, Heidi Greulich Dana-Farber as well as ballet Cancer Institute in Boston, MA and the broad Institute of Harvard and the Massachusetts Institute of technology in Cambridge, Massachusetts, Matthew Meyerson Harvard Medical School and Dana-Farber as well as ballet Cancer Institute in Boston, MA and the broad Institute of Harvard and the Massachusetts Institute of technology in Cambridge, Massachusetts.

This work is supported in part by NIH grants CA080942 (m.j.e.) and CA116020 (AND RELATED); M.J.E. is the recipient of a Scholar Award from leukemia and Lymphoma Society.

Yun et al.: "Structures Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: the mechanism of activation and transparency in differential inhibitor sensitivities."Publishing in cancer cell 11, 217--227, March 2007; DOI 10.1016/j. ccr. 2006.12,738.

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