At least 54 RTKs have been identified, and some, such as epidermal growth factor receptor (EGFR) have been implicated in glioblastomas. However, drugs that block EGFR have had limited success in delaying the progression of these and other virulent tumors. "Typically one elicits a positive initial response, but rarely durable cures," said DePinho, who is also a professor of medicine at Harvard Medical School. "Overall, the record of receptor tyrosine kinases inhibitors in these brain tumors has been somewhat disappointing."
Perhaps the problem was that other kinase pathways were also sending abnormal growth signals, acting as a redundant or backup source of growth simulation. "No one had looked to see how many receptor tyrosine kinases are activated at the same time in these cells," said Stommel.
The researchers tested 20 glioblastoma cell lines using an antibody array technique that measured the activation of 45 different RTKs at one time. In 19 of the 20 cell lines, three or more RTKs were activated at the same time, sending abnormal growth signals in triplicate to the nucleus. Moving from cell lines to fresh cells, the researchers saw the same multiple-RTK activity when they studied tumor samples from newly diagnosed patients.
The kinase inhibitor imatinib (Gleevec) had little effect on the errant signaling pathways when applied to the brain tumor cells. But when imatinib was given in combination with two other kinase inhibitors, erlotinib (Tarceva) and SU11274, traffic in the PI3K signaling pathway was eliminated, and the cancer cells died.
The study's findings "provide a rational explanation for the feeble clinical responses" when RTK inhibitors are
|Contact: Bill Schaller|
Dana-Farber Cancer Institute