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Jeff's targeted therapy has kept his advanced lung cancer at bay.
By mapping the interlocking structures of small molecules and mutated
protein "receptors" in non-small cell lung cancer (NSCLC) cells,
scientists at Dana-Farber Cancer Institute and their colleagues have
energized efforts to design molecules that mesh with these receptors,
potentially interfering with cancer cell growth and survival.
In a study published in the March issue of Cancer Cell,
researchers led by Michael Eck, MD, PhD, of Dana-Farber used X-ray
crystallography to determine the structure of two mutated forms of the
epidermal growth factor receptor (EGFR) in lung cancer cells. EGFR, a
protein known as a tyrosine kinase, plays a key role in relaying growth
signals within cells. When mutated, it can become overactive, leading to
excessive cell division and cancer.
"It turns out that in some cases, the very mutation that causes the
cancer in the first place is also the cancer's Achilles' heel," said
Eck, the paper's senior author. "We now see that inhibitors such as
gefitinib actually bind more tightly to some of the cancer-causing
mutants, even though they were originally developed to block the normal
Cai-Hong Yun, PhD, of Dana-Farber is the paper's first author.
Mutations in the EGFR kinase domain occur in approximately 16 percent
of NSCLCs, but at much higher frequencies in selected populations,
including nonsmokers, women, and East Asian patients. Laboratory and
clinical studies have shown that tyrosine kinase inhibitors are more
effective against some EGFR mutations than others, although the
molecular reasons for this are unclear. By developing a better
understanding of the effect of the mutations on inhibitor binding at a
structural level, it may be possible to develop more effective
In the current study, Eck and his colleagues analyzed the
three-dimensional structures of the normal and mutated versions of EGFR
bound to several different types of inhibitor molecules. They found
that two inhibitors the drug gefitinib (marketed as Iressa®), and a
compound called AEE788 — bind especially tightly to one of the mutated
forms, meaning these inhibitors are potentially more effective at
blocking the growth of cancer cells containing that mutation. In the
case of gefitinib, it bound 20 times more tightly to the L858R mutant
than to the normal, mutation-free EGFR.
The research team concluded that the particular EGFR mutation within
tumor cells determines which inhibitor molecules are likely to be able
to slow or stop the growth of those cells.
"Although structural divergence in the EGFR mutants may complicate
efforts to treat the disease, it may also present an advantage in that
it introduces the possibility of developing inhibitors that target
specific mutations, which should lead to more effective treatments,"
said Eck, who also an associate professor of Biological Chemistry and
Molecular Pharmacology at Harvard Medical School. "These targeted
therapies likely would be less toxic as they, in theory, would not
affect the normal functioning EGFR proteins."
In addition to Eck and Yun, the paper's other authors are Titus
Boggon, PhD, formerly of Dana-Farber and now at Yale University School
of Medicine; Yiqun Li and Michele Woo of Dana-Farber; and Heidi
Greulich, PhD, and Matthew Meyerson, MD, PhD, of Dana-Farber and the
Broad Institute of Harvard and Massachusetts Institute of Technology.
The research was supported with grants from the National Institutes
of Health, the Leukemia and Lymphoma Society, and American Society of
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National