Scientists at Dana-Farber Cancer Institute have uncovered the mechanism behind a promising new approach to cancer treatment: damaging cancer cells' DNA with potent drugs while simultaneously preventing the cells from repairing themselves.
The findings being reported in the Aug. 14 issue of Molecular Cell help explain the promising results being seen in clinical trials of compounds that force cancer cells with genetic damage to self-destruct instead of "resting" while their DNA undergoes repairs.
"What we have shown suggests that you can use these drugs to sensitize cancer cells to DNA-damaging chemotherapy," said Geoffrey Shapiro, MD, PhD, senior author of the report. "This is a mechanism by which these inhibitory drugs may be synergistic with DNA-damaging agents."
Interestingly, Shapiro said, when the same repair-blocking drugs were administered to normal, non-cancerous cells, the cells became less sensitive to DNA damage from a chemotherapy drug. This is an encouraging indication that repair-blocking drugs may selectively make cancer cells vulnerable to chemotherapy while protecting normal cells from DNA damage, the scientists said.
Cells' native capacity for fixing DNA damage is normally beneficial, but it can be problematic for cancer therapy as it enables tumor cells to become resistant to a number of standard drug agents. All cells progress through a series of phases -- called the cell cycle -- including quiescence, or resting, growth, and cell division. The transition from one phase to the next is regulated by "checkpoint" proteins that, among other things, are designed to prevent damaged, potentially dangerous cells from reproducing.
The body deals with DNA-damaged cells in two ways. It can order them to self-destruct through "programmed cell death," also known as apoptosis. Or, it can issue signals from the checkpoint proteins to put the cells into "cell cycle arrest," causing them to remain quiescent while the broken DNA is fixed before they resume normal activity.
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.