Unrelated protein activated to bypass blocked growth signal, new treatment approach suggested
Pasi A. Jänne, MD, PhD
An international research team, led by investigators from the
Massachusetts General Hospital (MGH) Cancer Center and Dana-Farber
Cancer Institute, 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 Dana-Farber, 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 Dana-Farber 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).
"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