Discovery explains cancer chemotherapy resistance, offers solution – ScienceDaily


Researchers have discovered a new pathway that explains how cancer cells become resistant to chemotherapies, which in turn offers a potential solution to preventing chemotherapy.

Fluoridation of experimental DNA fibers was used to detect the speed of DNA replication forks.

The research describes for the first time how a type of enzyme – previously known for its roles in DNA repair – prevents DNA damage in cancer cells, making them tolerant of chemotherapy drugs.

“They provide us with tools to manipulate and then break down chemoresistance in cancer cells,” said Markus Smolka, interim director of the Weill Institute for Cellular and Molecular Biology and professor of molecular biology and genetics in the College of Agriculture and Life Sciences. Diego Depeto, a former postdoctoral researcher in Smolka’s lab who is currently at the University of Bern in Switzerland, is the paper’s first author.

Many anticancer drugs work by creating clumps on the DNA of cancer cells as they multiply. During replication, DNA strands in a separate double helix intertwine into two single strands so that each strand can be transcribed, eventually resulting in a new double helix. The junction at which this separation and transcription occurs is called the replication fork, which decompresses the double helix.

If these transcription forks are cars on the road, then chemotherapy drugs can be imagined as obstructions that interfere with the flow of cars, thus stopping reproduction and breaking down DNA. But cancer cells have a way of slowing down these forks, allowing them to avoid such collisions and protect their DNA, resulting in drug tolerance.

This study indicates, for the first time, how a kinase (enzyme) called DNA-PKcs acts as a sensor when a fork is stressed by clumps, promoting fork slowing and chemoresistance.

DNA-PKcs has been known for its role in DNA repair associated with the generation of immune system antibodies and radiation resistance. But this is the first time that the kinase has been associated with slowing down the replication fork, a process called fork reversal.

“It’s a whole new way to think about the effect of this kinase,” Smolka said. “It’s not DNA repair in this case; it’s slowing down the forks to prevent breaks from happening in the first place.”

The findings open the door to new cancer treatments, as inhibitors of DNA-PKcs already exist and are being used in clinical trials along with radiotherapy. In those therapies, radiation destroys the DNA of cancer cells, and it was widely believed that inhibiting DNA-PKcs would limit cell repair. But DNA-PKcs inhibitors don’t work well in this context, because cancer cells have other ways to repair themselves.

This study provides early evidence that the DNA-PKcs inhibitor can be effective in combination with chemotherapies, as chemotherapeutic drugs create blocks of DNA replication, and the inhibitor prevents slowing down of transcriptional forks that lead to chemoresistance.

In the study, the researchers used an assay to detect DNA-PKcs kinases at replication forks. Then they used a fluorescent color DNA fiber assay, so that the faster the transcription forks moved, the longer the fibers became. In the presence of chemotherapeutic drugs, the fibers were short, indicating slowed replication forks. But when the dampers were added, the fibers remained longer, indicating that the forks were moving at higher speeds.

Co-author Massimo Lopez, an expert in transcription stress at the University of Zurich, captured images that confirmed that replication forks are no longer reversed and slowed down in the presence of kinase inhibitors. The team also demonstrated that cancer cells became diseased or deteriorated when chemotherapy and inhibitors were used together.

Finally, BRCA2-deficient breast cancers can become resistant to the chemotherapeutic drugs used to treat them, and fork reversal has been known to be implicated in the resistance. In this study, when researchers applied DNA-PKcs inhibitors to BRCA2-deficient breast cancer cells that were resistant to treatment, the cells regained sensitivity to the treatment.

“This is another way to confirm that being able to prevent hysteresis and fork inversion through inhibitors of DNA-PKcs seems like a really good way to manipulate chemoresistance,” Smolka said.

In future work, the research team will investigate how cells sense the stress of the replication fork and what proteins the DNA-PKcs interact with to slow these forks.

Sven Rottenberg, a research into cancer treatment resistance at the University of Bern, is a co-author.

The study was funded by the Fleming Research Foundation, the National Institutes of Health, the Swiss National Science Foundation, the European Union, and the Wilhelm Sander Foundation.

Story source:

Materials Introduction of Cornell University. Original by Krishna Ramanujan, courtesy of the Cornell Chronicle. Note: Content can be modified according to style and length.



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