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 bro
Contact: Sue McGreevey
Massachusetts General Hospital