Targeted cancer drugs may work by disrupting
balance of cellular signals
Study supports new model of drug
action that may explain problems, suggest new approaches
BOSTON - November 13, 2006 - Targeted cancer therapy drugs
like Gleevec (imatinib) and Tarceva (erlotinib), which destroy tumors
by interfering with specific proteins or protein pathways, may disrupt
the balance between critical cellular signals in a way that leads
to cell death. In the November issue of Cancer Cell, researchers
from the Massachusetts
General Hospital Cancer Center present evidence for their theory,
which runs counter to an alternative hypothesis called 'oncogene
addiction.' Better understanding these drugs' mechanism of operation
could help surmount current limitations on their usefulness and
lead to the discovery of additional protein targets.
"It looks like these drugs reduce the activity of their target
proteins in such a way that cell-death signals remain high while
survival signals drop," says Jeffrey Settleman, PhD, director
of the Center
for Molecular Therapeutics at the MGH Cancer Center, senior
author of the report. "This model gives us clues that could
lead to more successful treatment strategies and answer questions
about the limited effectiveness these drugs have had."
It has become apparent that certain forms of cancer depend on mutations
in specific genes, called oncogenes, for their development and survival.
These include the EGFR gene in non-small-cell lung cancer and a
gene called BCR-ABL in leukemia. Both of those genes code for proteins
called kinases, which regulate the processing of key cellular signals.
The cancer-associated mutations overactivate the kinases in ways
that lead to the uncontrolled growth of a tumor.
Drugs that have been specifically designed to interfere with the
activity of these kinases - Gleevec targets the BCR-ABL protein
and both Tarceva and Iressa (gefitinib) inhibit EGFR activity -
have been very successful in limited numbers of patients. But as
yet researchers have not understood the molecular mechanism underlying
these drugs' activity, information that might expand their usefulness
to a broader patient population and address problems of resistance
that can develop. The 'oncogene addiction' theory proposes that
the internal circuitry of tumor cells becomes so reliant on the
oncogenic protein or the pathway it controls that the cells die
if kinase activity is suppressed.
Since kinases control two types of cellular signals - some leading
to cellular survival, others to cell death - the MGH team proposed
an alternative explanation: that survival signals drop quickly after
kinase activity is suppress, releasing their control over persistant
cell-death signals. To test this hypothesis, they conducted several
experiments using oncogene-expressing cell lines. In lines expressing
tumor-associated versions of BCR-ABL, EGFR, or another kinase called
Src, the survival-associated signals dropped quickly after kinase
activity was suppressed, while cell-death signals were maintained.
Because the oncogenes had been artificially introduced into those
cell lines, the researchers then tested their model in human lung
cancer cells with the EGFR mutation. Again, kinase suppression,
this time by application of Iressa, produced a rapid reduction in
survival signals and eventual cell death as cell-death signals rose.
A subsequent experiment with the Src cell line showed that cells
pushed into a malignant form by expression of the mutant kinase
could survive after Src activity was suppressed if a survival signal
was supplied from another source, implying that the cells are not
totally dependent on the oncogene's activity.
"While all of these drugs have different targets, they appear
to act in a similar way, causing a reduction in survival-promoting
proteins while apoptotic [cell-death promoting] signals persist
and drive the cells towards death," Settleman says. "We
suggest that the term 'oncogenic shock' may be a more accurate way
to describe a process in which the very thing that kept the tumor
alive - overexpression of a kinase - is turned against itself when
the balance is disrupted to allow the cell-death signals to predominate."
The new model also could explain why targeted drugs have not worked
well in combination with standard chemotherapy drugs, which shut
down the cell cycle and may actually halt the cell-death process,
he adds. And if survival and apoptotic signals do drop and recover
at different rates, giving these medications in a cyclic fashion,
rather than continuously as currently prescribed, might better take
advantage of the temporal windows of vulnerability and could possibly
avoid drug resistance. Drugs that target the survival and cell death
signals themselves may present another new strategy.
"These findings explain why activated kinases are such good
targets and support the importance of searching for more,"
adds Settleman, a professor of Medicine at Harvard Medical School.
"More than 500 kinases have been identified, but we only have
a half-dozen targeted kinase inhibitors. Finding new treatment targets
and identifying the patients whose tumors have those kinases may
bring us closer to the goal of truly personalized cancer treatment."
The report's lead author is Sreenath Sharma, PhD, of the MGH Cancer
Center, and the co-authors are Patrycja Gajowniczek, Inna Way, Diana
Lee, Marie Classon, PhD, and Daniel Haber, MD, PhD, of the MGH;
and Jane Jiang and Yuki Yuza, Dana-Farber Cancer Research Institute.
The study was supported by grants from the National Institutes of
Health, the V Foundation and a Saltonstall Scholar Award.
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. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
Media Contact: Sue
McGreevey, MGH Public Affairs
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