|
New mechanism identified for resistance
to targeted lung cancer drugs
Unrelated protein activated to bypass
blocked growth signal, new treatment approach suggested
BOSTON - April 26, 2007 - 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, 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 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.
Media Contact: Sue
McGreevey, MGH Public Affairs
Robbin Ray, DFCI
Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
|
|
|
