Navigation Links
Study supports DNA repair-blocker research in cancer therapy

BOSTON--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.

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 the repair process?

The investigators showed that a key player in DNA repair -- the BRCA1 protein best known in its mutated form as an inherited breast cancer risk factor -- couldn't fulfill its mission in lung cancer cells lacking cdk1.

Going a step further, the researchers administered a cdk-inhibiting drug to lung cancer cells that hadn't been stripped of their cdk1 protein. In these cells, BRCA1 activity was reduced, demonstrating that the cdk inhibitors work in large part by keeping BRCA1 on the sidelines, weakening the DNA repair team.

"These results explain the observations seen in clinical trials" currently being conducted at Dana-Farber and elsewhere, said Shapiro, who is also an associate professor of medicine at Harvard Medical School. "The data give us confidence to go ahead with testing of cdk inhibitors in combination with DNA-damaging chemotherapy."


Contact: Bill Schaller
Dana-Farber Cancer Institute

Related biology news :

1. K-State lab gives researchers the tools to study porcine circovirus associated diseases
2. New study shows that cocoa flavanols can be preserved during cooking and baking
3. New study suggests possible genetic links between environmental toxins and multiple myeloma
4. New study reveals unexpected relationship between climate warming and advancing treelines
5. Stimulus funding helps K-State biochemist study eyes lens in diabetes, galactosemia patients
6. U of M study identifies risk factors of disordered eating in overweight youth
7. K-State researcher, collaborators study virulence of pandemic H1N1 virus
8. Study links virus to some cases of common skin cancer
9. Douglas-fir, geoducks make strange bedfellows in studying climate change
10. 1 in 6 health workers wont report in flu pandemic -- study by Ben-Gurion U. researchers
11. Study shows cancer vaccines led to long-term survival for patients with metastatic melanoma
Post Your Comments:
(Date:10/29/2015)... , Oct. 29, 2015  The J. Craig Venter ... titled, "DNA Synthesis and Biosecurity: Lessons Learned and Options ... of Health and Human Services guidance for synthetic biology ... --> --> ... has the potential to pose unique biosecurity threats. It ...
(Date:10/29/2015)... -- Connected health pioneer, Joseph C. Kvedar , MD, ... and wellness, and the business opportunities that arise from ... of Healthy Things . Long before health and ... Kvedar, vice president, Connected Health, Partners HealthCare, was creating ... from the hospital or doctor,s office into the day-to-day ...
(Date:10/27/2015)... , Oct. 27, 2015 In the present ... of concern for various industry verticals such as banking, ... to the growing demand for secure & simplified access ... ,sectors, such as hacking of bank accounts, misuse of ... equipment such as PC,s, laptops, and smartphones are expected ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... DIEGO , Nov. 24, 2015 Halozyme Therapeutics, Inc. ... Healthcare Conference in New York on Wednesday, ... Helen Torley , president and CEO, will provide a corporate ... New York at 1:00 p.m. ET/10:00 a.m. PT ... and investor relations, will provide a corporate overview. --> ...
(Date:11/24/2015)... Inc., a worldwide provider of clinical research services headquartered in ... has set a new quarterly earnings record in Q3 of 2015.  ... Q3 of 2014 to Q3 of 2015.   ... the establishment of an Asia-Pacific office to ... and Mexico , with the establishment ...
(Date:11/24/2015)... , November 24, 2015 ... market research report released by Transparency Market Research, the ... at a CAGR of 17.5% during the period between ... Market - Global Industry Analysis, Size, Volume, Share, Growth, ... non-invasive prenatal testing market to reach a valuation of ...
(Date:11/24/2015)... ... November 24, 2015 , ... InSphero AG, the leading supplier of ... has promoted Melanie Aregger to serve as Chief Operating Officer. , Having ... management team and was promoted to Head of InSphero Diagnostics in 2014. ...
Breaking Biology Technology: