Repair-blocking drugs are designed to squelch the checkpoint proteins' signals, preventing the chemotherapy-damaged cancer cells from initiating the rest phase and undergoing repairs. Instead, they're forced to progress through the cell cycle and, because of their broken DNA, self-destruct through apoptosis. Accordingly, the tumor loses much of its power to develop resistance to drugs that attack DNA.
When a cell senses damage to its DNA, it triggers a series of events, called a "checkpoint cascade." Two major checkpoint proteins, cdk1 and cdk2, send signals that stop the cell cycle. At the same time, a flock of repair proteins are recruited to the site of the DNA damage.
In clinical trials aimed at disrupting the DNA-repair process, scientists are using inhibitor drugs to block cdk signaling. The drugs cause the damaged cells to bypass the checkpoint control and continue to grow and divide -- and ultimately die. Those trials are showing promising results, said Shapiro. He and his colleagues, in their new paper, demonstrate the molecular mechanism by which cdk inhibitors work, and they say that the explanation bodes well for continued research on the drugs.
Previously, it was known that cdk1 and cdk2 were virtually interchangeable in most cancer cells, and if one of the proteins malfunctioned or was knocked out, the other could compensate for it.
To find out if this overlap might pose a problem for cdk-inhibitor therapy, the researchers disabled just one of the proteins -- cdk1 -- in cultured lung cancer cells and treated the cells with cisplatin, a DNA-damaging agent. Even though the partner cdk2 protein was still active, the cdk1-depleted cancer cells failed to stop, rest, and repair themselves; it was evident that they were now more vulnerable to death from the cisplatin.
But how did the loss of just the one checkpoint protein disrupt t
|Contact: Bill Schaller|
Dana-Farber Cancer Institute