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Tuesday, January 19, 2010
Even when their tumors are
shrinking in response to therapy, some non-small cell lung cancer (NSCLC)
patients have a scattering of cancer cells that are undeterred by the drug,
causing the tumor to resume its growth, Dana-Farber Cancer Institute and
Massachusetts General Hospital (MGH) Cancer Center scientists report in the
January issue of Cancer Cell. The findings
suggest that identifying such patients and treating them with a combination of
drugs from the very start of therapy can produce longer remissions.
The study involves NSCLC tumors which are driven by a mutation in the gene EGFR. Such tumors, which account for about 12 percent of all NSCLC cases in the United States, often recede when treated with a tyrosine kinase inhibitor such as Tarceva or Iressa, which targets the faulty EGFR protein.
few years ago, this same group of investigators showed that NSCLCs being held
in check by Tarceva can switch on an alternate growth circuit if they have too
many copies of a gene called MET.
Such tumors are considered Tarceva- and Iressa-resistant.
the new paper, investigators led by Pasi
Jänne, MD, PhD, of Dana-Faber, and Jeffrey
Engelman, MD, PhD, of MGH, found that some patients with EGFR-mutant lung cancers harbor a small
number of tumor cells with an overabundance, or "amplification," of MET even before treatment with a
tyrosine kinase inhibitor, and that those few cells are enough to spark drug
resistance. One of the triggers for resistance, the researchers found, is HGF,
a ligand or "hook" that activates the MET protein.
HGF works through two entirely different channels to produce drug resistance,
the authors report. First, it can generate cell-growth signals through a
protein called GAB1. Second, it expands the number of MET-amplified cancer cells, ensuring they will become the dominant
type in the lung tumors.
only can HGF spur cell growth on its own, it can speed up the process by which MET-amplified cells emerge and take over
the composition of the tumor," says Jänne, who was co-senior author of the
paper with Engelman. In about 20 percent of NSCLC patients who are resistant to
Tarceva the mechanism is amplification of MET,
and in another 20 percent it may involve HGF.
findings suggest that patients whose NSCLC tumors harbor even a few MET-amplified cells prior to treatment
would benefit from drugs that specifically target those cells, in combination
with a tyrosine kinase inhibitor. Jänne notes that such drugs are already being
studied in clinical trials.
findings provide a strong rationale for combination treatment strategies as
initial therapies for some patients," Jänne remarks. "This is especially the
case in patients with evidence of pre-existing MET amplifications."
adds, "A thorough analysis of a patient's cancer prior to treatment can
establish how it would ultimately develop resistance to therapy, allowing us to
tailor treatment with greater precision to prevent resistance. For example, cancers found to harbor a small
population of cells with pre-existing MET
amplification will likely benefit from adding MET inhibitors to initial
treatment. Those without such cells may
not benefit, and these patients can avoid the added toxicity of MET inhibitors
and instead focus on other strategies to prevent their cancers from becoming
resistant." Engelman is an assistant
professor of medicine and Jänne an associate professor of medicine at Harvard
The study was
supported by grants from the National Institutes of Health, American
Association for Cancer Research, the V Foundation, American Cancer Society,
Hazel and Samuel Bellin Research Fund, and the Ellison Foundation.
study's co-lead authors were Alexa Turke of MGH, and Kreshnik Zejnullahu, of
Dana-Farber. Co-authors include Yi-Long
Wu, of Guangdong General Hospital, Guangzhou, China; Youngchul Song, Dora
Dias-Santagata, PhD, Eugene Lifshits, Lecia Sequist, MD, MPH, Sara Akhavanfard,
MD, Beow Yeap, and A. John Iafrate, MD, PhD, of MGH; Luca Toschi, MD, Andrew
Rogers, and Marzia Capelletti of Dana-Farber; Tony Mok, MD, of the Chinese
University of Hong Kong; Neal Lindeman, MD, Carly Murphy, Yun Xiao, and Charles
Lee, PhD, of Brigham and Women's Hospital; and James Christensen, of Pfizer
Global Research and Development, La Jolla, Calif.
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 Cancer Institute.
established in 1811, is the original and largest teaching hospital of Harvard
Medical School. The MGH conducts the
largest hospital-based research program in the United States, with an annual
research budget of more than $600 million and major research centers in AIDS,
cardiovascular disease, cancer, computational and integrative biology,
cutaneous biology, human genetics, medical imaging, neurodegenerative
disorders, regenerative medicine, systems biology, transportation biology, and
Katie Marquedant, email@example.com, 617 726-0337
Bill Schaller, Dana-Farber, 617 632-5357
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