New class of drugs may treat lung tumors
resistant to Iressa and Tarceva
Study reveals complex mechanism underlying
resistance to targeted lung cancer drugs
BOSTON - May 16, 2005 - A new class of drugs that block the
epidermal growth factor receptor (EGFR) on lung cancer cells may
get around the growing problem of resistance to targeted therapy
drugs like Iressa and Tarceva. In a report to appear in Proceedings
of the National Academy of Science, researchers from Massachusetts
General Hospital (MGH) Cancer Center and colleagues from Wyeth
Pharmaceuticals research division describe finding how drugs called
irreversible EGFR inhibitors apparently avoid resistance and may
offer patients longer term remission. The study has received early
online release on the PNAS website.
"These irreversible inhibitors form an unbreakable bond with
the EGFR molecule," says Daniel Haber, MD, PhD, director of
the MGH Cancer Center and senior author of the PNAS paper.
"The initial group of EGFR inhibitors can fall off the receptor,
but once the irreversible inhibitors bind, the receptor is permanently
out of commission." The researchers also discovered a new mechanism
underlying the development of resistance, one which the new drugs
may be able to avoid.
EGFR inhibitors, 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. In 2004 MGH
researchers found that a particular set of mutations in the
EGFR molecule could identify patients whose tumors would respond
to Iressa, which early clinical trials indicated was effective in
less than 15 percent of patients. The identified mutations magnified
the cells' response to growth factor, fueling tumor growth, but
they also increased tumors' sensitivity to Iressa. Subsequent research
found that similar mutations were associated with sensitivity to
Although results for those patients who did respond to these EGFR
inhibitors were often rapid and dramatic, they were also short lived,
lasting for an average of 6 to 8 months. Researchers at several
centers attributed this resistance to a secondary mutation in a
different part of the EGFR molecule found in some but not all resistant
patients. These secondary mutations are similar to mutations associated
with acquired resistance to Gleevec and other targeted cancer therapy
drugs. The current study was designed to further investigate those
mutations and the mechanisms underlying treatment resistance.
The researchers first conducted a detailed genetic analysis of tumor
samples from two patients whose cancer had recurred after initially
responding to Iressa treatment. The initial sensitizing mutation
was found in all recurrent tumor cells from both patients, but the
resistance-associated secondary mutation was found in only 20 percent
of cells from one patient and virtually no cells from the other
patient, confirming that other resistance mechanisms must exist.
The team then started with Iressa-sensitive NSCLC cells and created
multiple lines of cultured Iressa-resistant tumor cells. None of
these resistant lines acquired a secondary mutation in EGFR, but
they appeared to have changes in the intricate way the receptor
receives chemical signals and transmits them into the cell.
"These cells go through a complex process of internalization,
in which the receptors take up their ligand [signalling molecule]
on the cell surface, move inside the cell, release the ligand and
then move back to the cell membrane,"says Haber, a professor
of Medicine at Harvard Medical School. "We're starting to appreciate
that a very slight change in the regulation of this process can
have a great impact, and much of this had been predicted by several
researchers studying EGFR regulation."
In what they consider their most critical observation, the investigators
also found that NSCLC cells that have become resistant to Iressa,
through either the secondary EGFR mutation or altered receptor processing,
continue to be sensitive to a new class of compounds that bind more
tightly and irreversibly to EGFR. Haber and his colleagues believe
that the stronger binding of these "irreversible inhibitors"
overcomes both the structural change resulting from the secondary
EGFR mutation and the changes in receptor processing. Not only are
Iressa-resistant NSCLC cells still sensitive to these irreversible
inhibitors, but very few NSCLC cells treated with these new drugs
ever become resistant to the new drugs.
One of the irreversible EGFR inhibitors used in this study - HKI-272,
manufactured by Wyeth - is already in a phase 1 clinical trial.
And MGH Cancer Center researchers are planning to lead a multi-institutional
phase 2 trial in NSCLC patients whose tumors have sensitizing EGFR
mutations but have become resistant to Iressa or Tarceva.
Co-lead authors of the PNAS study are Eunice Kwak, MD, PhD, Raffaella
Sordella, PhD, Daphne Bell, PhD, and Nadia Godin-Heymann, PhD, of
the MGH Cancer Center. Additional co-authors are Ross Okimoto, Brian
Brannigan, Patricia Harris, David Driscoll, Panos Fidias, MD, Thomas
Lynch, MD, Sreenath Sharma, PhD, Kurt Isselbacher, MD, and Jeffrey
Settleman, MD, of the MGH Cancer Center; and Sridhar Rabindran,
PhD, John McGinnis, PhD, and Allan Wissner, PhD, of the Wyeth Pharmaceuticals
research division. The research was supported by grants from the
National Institutes of Health, the Doris Duke Charitable Foundation,
the Sandler Family Foundation, the V Foundation, the Samuel Waxman
Cancer Research Foundation, the Saltonstall Scholarship, the Cole-Angelus
Fund, Romaine Fund, and Sue's Fund for Lung 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 more than $450 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials