[ad_1]
Many chemotherapy drugs kill cancer cells by severely damaging their DNA. However, some tumors can resist this damage by relying on a DNA repair pathway that not only allows them to survive, but also introduces mutations that help cells become resistant to further processing.
Researchers at MIT and Duke University have discovered a potential drug that could block this remedy. "This compound increases the number of cells killed with cisplatin and prevents mutagenesis, which we expected by blocking this pathway," says Graham Walker, professor of biology at the American Cancer Society, professor of biology at MIT, professor at the Howard Hughes Institute, lead authors of the study.
When they treated mice with this compound with cisplatin, a DNA-damaging drug, the tumors shrank much more than those treated with cisplatin alone. Tumors treated with this combination should not develop new mutations that make them resistant to drugs.
Cisplatin, which has been used as the first treatment option for at least a dozen types of cancer, often successfully destroys tumors, but often repels after treatment. Drugs that target the mutagenic DNA repair pathway that contributes to this recurrence could help improve the long-term effectiveness of cisplatin, but also other chemotherapy drugs damaging the immune system. DNA, the researchers said.
"We are trying to improve the functioning of the therapy and we also wish to make the tumor consistently responsive to repeated dose therapy," said Michael Hemann, badociate professor of biology, a member of the Koch Research Institute. on cancer and integrator of MIT, and a senior author of the study.
Pei Zhou, professor of biochemistry at Duke University, and Jiyong Hong, professor of chemistry at Duke, are also the main authors of the article that appears in the June 6 issue of Cell. The lead authors of the paper are Jessica Wojtaszek, a former Duke graduate student, Nimrat Chatterjee, MIT postdoc, and Javaria Najeeb, research badistant for Duke.
Overcoming resistance
Healthy cells have multiple repair pathways that can accurately eliminate the damage to the cells' DNA. When cells become cancerous, they sometimes lose one of these precise DNA repair systems. They therefore strongly depend on an alternative adaptation strategy known as translesion synthesis (TLS).
This process, which Walker has been studying for many years in various organisms, is based on specialized TLS DNA polymerases. Unlike normal DNA polymerases used to replicate DNA, these TLS DNA polymerases can essentially copy to the damaged DNA, but the copy they perform is not very accurate. This allows the cancer cells to survive treatment with a DNA damaging agent, such as cisplatin, and to acquire many additional mutations that can make them resistant to further processing.
"Because these TLS DNA polymerases are actually prone to errors, they are responsible for almost all mutations induced by drugs such as cisplatin," says Hemann. "It is very well established that with the first-line chemotherapy we use, if they do not cure you, they will make you worse."
One of the main TLS DNA polymerases required for translesion synthesis is Rev1 and its main function is to recruit a second TLS DNA polymerase which consists of a complex of Rev3 and Rev7 proteins. Walker and Hemann looked for ways to disrupt this interaction, hoping to derail the repair process.
In two studies published in 2010, the researchers showed that if they used RNA interference to reduce Rev1 expression, cisplatin treatment would become much more effective against lymphoma and lung cancer in mice. Although some of the tumors recurred, the new tumors did not resist cisplatin and could be killed again with a new treatment cycle.
After showing that interfering with the synthesis of translesion could be beneficial, the researchers looked for a small molecule drug that would have the same effect. Under Zhou's leadership, the researchers badyzed approximately 10,000 potential drug compounds and identified one that tightly binds to Rev1, preventing it from interacting with the Rev3 / Rev7 complex.
The interaction of Rev1 with the Rev7 component of the second TLS DNA polymerase had been considered "unsustainable" as it occurs in a very shallow pocket of Rev1, with few features allowing a drug to break down. hang easily. However, to the surprise of the researchers, they found a molecule that binds two molecules of Rev1, one at each end, and joins them together to form a complex called dimer. This dimerized form of Rev1 can not bind to TLS Rev3 / Rev7 DNA polymerase, so that translesion synthesis can not occur.
Chatterjee tested the compound with cisplatin in several types of human cancer cells and found that the combination killed many more cells than cisplatin alone. And, the cells that survived had a greatly reduced ability to generate new mutations.
"Because this novel translesion synthesis inhibitor targets the mutagenic ability of cancer cells to resist treatment, it can potentially solve the problem of cancer relapse, where cancers continue to develop from new mutations and together constitute a major challenge in the treatment of cancer, "said Chatterjee.
A powerful combination
Chatterjee then tested the drug combination in mice with human melanoma and found that the tumors had decreased much less than those treated with cisplatin alone. They now hope that their discoveries will lead to further research on compounds that could act as inhibitors of translesion synthesis to enhance the destructive effects of existing chemotherapy drugs.
Zhou's laboratory at Duke is working on the development of compound variants that could be developed for possible tests on human patients. Meanwhile, Walker and Hemann are looking more closely at how the pharmaceutical compound works, which they believe could help determine the best way to use it.
"This is a major goal for the future: to identify in what context this combination therapy will work particularly well," said Hemann. "We hope that our understanding of how they work and when they coincide will coincide with the clinical development of these compounds, so when they are used, we will understand which patients they should receive."
The research was funded, in part, by an Outstanding Investigator Award from the National Institute of Environmental Health Sciences and by Walker, as well as grants from the National Cancer Institute, Stewart Trust. and the Center for Precision Cancer Medicine at MIT.
Source link
