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

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 controls 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."

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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 System, a Boston-based integrated health care delivery system.


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