这篇文章介绍了一种药，可以防止IRESSA抗药(同时服用)，本来这药是解决其他药抗药的，后来发现可以防止IRESSA抗药，此药已进入FDA预批准阶段，但愿我们的老人还能等到这一天。
Public release date: 26-Apr-2007
Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
New mechanism identified for resistance to targeted lung cancer drugsUnrelated protein activated to bypass blocked growth signal, new treatment approach suggested
An international research team, led by investigators from the
Massachusetts General Hospital (MGH) Cancer Center and Dana-Farber
Cancer Institute (DFCI), has found a new way that some lung tumors
become resistant to treatment with targeted therapy drugs like Iressa
and Tarceva. Their report, which will appear in the journal Science and
is receiving early online release, describes a totally new resistance
mechanism that may apply to many types of cancer. It also suggests a
treatment strategy for patients with these resistant tumors.
"We found that, for about 20 percent of patients with tumors that become
resistant to Tarceva or Iressa, resistance is caused by the genetic
activation of an oncogene that is not the normal target of the drug,
which is something that has never been seen before," says Jeffrey
Engelman, MD, PhD, scientific director of the MGH Center for Thoracic
Cancers, the paper's lead author.
"Importantly, we also identified a potential new way to treat these resistant tumors with
combination therapy directed against both protein targets," adds Pasi
A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology at DFCI,
the study's senior author.
Drugs like Iressa (gefitinib) and
Tarceva (erlotinib) are used to treat advanced non-small-cell lung
cancer (NSCLC), the leading cause of cancer deaths in the U.S. They act
by blocking the epidermal growth factor receptor (EGFR), a molecule on
the surface of cancer cells. In 2004 research teams from MGH and DFCI
found that only tumors in which the EGFR gene has been mutated in a way
that magnifies the cells' response to the growth factor, a process that
fuels tumor growth, were sensitive to treatment with these drugs.
Although tumors that respond to EGFR inhibitors do so rapidly and dramatically,
eventually the tumors become resistant and resume growing. About half
the time, a secondary mutation that interferes with the drugs' binding
to the receptor develops within the EGFR gene. A new group of so-called
irreversible EGFR inhibitors that permanently bind to the protein are
currently being tested in clinical trials. But what leads to other
cases of resistance has been unknown, and the current study was
designed to discover additional mechanisms.
To do so, the investigators modeled in a laboratory setting what happens in lung
cancer patients; they used a line of NSCLC cells with the sensitizing
EGFR mutation and created a cell line resistant to treatment with
Iressa. In a number of experiments comparing the resistant line with
still-sensitive cells, they focused on the cell signalling pathway
controlled by EGFR. In earlier research, Engelman and colleagues had
found that the growth signal that starts with EGFR works through a
related protein called ERBB3.
The current study showed that,
in some of the resistant cells, ERBB3 is activated by amplification of
a different oncogene called MET, in essence bypassing the blockage of
EGFR. Analysis of samples from patients whose tumors became resistant
after initially responding to Iressa revealed that MET was amplified in
resistant samples from 4 of 18 patients. Although treating resistant
cell lines with either Iressa or a MET inhibitor did not stop tumor
growth, treatment with both agents did induce cell death.
"This
method of reactivating the EGFR signalling pathway with MET may be a
common resistance mechanism in other therapies that target receptors of
the ERBB family, which are used against breast cancer, colon cancer,
head and neck cancer, and the brain tumor glioblastoma multiforme,"
says Jänne, who is an assistant professor of Medicine at Harvard
Medical School (HMS). Engelman is an HMS instructor of Medicine.
"Our
results suggest that, when patients' tumors become resistant, repeat
biopsies to identify which resistance mechanism is involved will be
critical and could help us develop effective therapies for those
resistant tumors," adds co-author Lewis Cantley, PhD, of the Beth
Israel Deaconess Medical Center.
To that end, the
investigators are working on a research protocol for combined treatment
with FDA-approved EGFR inhibitors and with MET inhibitors, which are in
preapproval trials against other types of cancer. They also plan to
analyze a larger number of resistant samples to get a clearer idea of
the frequency of this resistance mechanism.
###
Additional
co-authors of the Science report are Kreshnik Zejnullahu, Joon Oh Park,
MD, PhD, Xiaojun Zhao, PhD, Alison Holmes, Andrew Rogers and Bruce
Johnson, MD, of Dana-Farber; Tetsuya Mitsudomi, MD, and Takayuki
Kosaka, MD, Aichi Cancer Center Hospital, Nagoya, Japan; Youngchul Song
and Christopher-Michael Gale; Courtney Hyland, Neal Lindeman, MD, and
Charles Lee, PhD, Brigham and Women's Hospital; James Christensen, PhD,
Pfizer Global Research and Development; Federico Cappuzzo, MD,
Instituto Clinico Humanitas, Rozzano, Italy; and Tony Mok, MD, Chinese
University of Hong Kong. The study was supported by grants from the
National Institutes of Health, including the National Cancer Institute;
the American Cancer Society, the American Association for Cancer
Research; the International Association for the Study of Lung Cancer;
and the Italian Association for Cancer Research.
Massachusetts General Hospital (www.massgeneral.org),
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 nearly $500 million and major research centers in AIDS,
cardiovascular research, cancer, computational and integrative biology,
cutaneous biology, human genetics, medical imaging, neurodegenerative
disorders, regenerative medicine, transplantation biology and
photomedicine.
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), a designated comprehensive cancer center by the
National Cancer Institute.
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