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.