A Closer Look at Chemotherapy Resistance

 Chemotherapy is a type of cancer treatment that works by stopping or slowing down the growth of cancer cells. However, a patient may respond positively to the treatment for only a certain period of time before it is no longer effective and the tumor begins to grow again. This is known as chemotherapy resistance. Anti-cancer drugs work by creating blocks on the DNA of cancer cells as they replicate. In DNA replication, the double helix unwinds into two strands so that each strand can be copied. The area where the unwinding and copying occurs is called the replication fork. Chemotherapy drugs interfere with the replication fork to prevent replication, but cancer cells have a way to prevent this.

 

Researchers at Cornell University have discovered a novel pathway that explains how chemotherapy resistance occurs. A kinase called DNA-PKcs was found to act as a sensor when a replication fork was stressed due to blocks, and it promotes the slowing of the fork and chemoresistance. DNA-PKcs are known for their DNA repair related to immune system antibody generation and resistance to radiation, but never has it been associated with slowing down a replication fork, which is also called fork reversal. Fork reversals prevent breaks from happening in the DNA, allow for the tolerance of DNA damage, and suppress genomic instability. This allows cancer cells to withstand anti-cancer drugs. In their study, an assay was used to detect the DNA-PKcs kinase at replication forks. After, a DNA fiber assay with fluorescent colors was used to determine the speed of DNA replication forks. The faster the replication forks moved, then the longer the DNA fibers with fluorescence were. When DNA-PKcs inhibitors were added, the fibers were longer, which indicated the forks were moving at faster speeds. Additionally, the researchers saw that the use of chemotherapy and DNA-PKcs inhibitors together significantly degraded cancer cells. They tested their findings on BRCA2 deficient breast cancers, which are known to be able to have chemotherapy resistance and that fork reversal is involved in the resistance. When DNA-PKcs inhibitors were applied to the BRCA2 deficient breast cancer cells that had chemotherapy resistance, the cells regained sensitivity to the treatment. 

 

The solution to chemotherapy resistance right now is to attempt to treat patients with combinations of different drugs. However, this study suggests that using DNA-PKcs inhibitors along with current chemotherapy drugs can be an effective way to treat chemotherapy resistance. DNA-PKcs inhibitors already exist and are being used in clinical trials for radiation therapies, so this treatment could potentially be used in somewhat of the nearby future and can be more effective than the strategy now. Cancer has countless forms with differing causes and treatment approaches, so it is always nice to see scientists learning more about the pathways involved to discover new treatments. 

 

Posted by Tiffany Pham (6)

 

https://www.sciencedaily.com/releases/2022/09/220920141429.htm

Comments

  1. AnonymousOctober 25, 2022 at 2:19 PM

    Hi Tiffany! I found your post to be really informative as I didn’t realize that cancer patients could develop resistance to chemotherapy. It’s important that scientists learn more about how processes like chemotherapy resistance work so that they can create safe and effective treatments in the future. Are certain types of cancer more likely to cause chemotherapy resistance?

    - Sarah Belcher

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    1. AnonymousOctober 28, 2022 at 12:53 PM

      Hi Sarah! I couldn't really find any research about if certain types of cancer are more likely to cause chemotherapy resistance. However, I did read that chemotherapy resistance occurs differently depending on the cancer and that cancers can develop resistance over time even if they are initially susceptible to chemotherapy. This can happen through DNA mutations or other metabolic changes that can promote drug inhibition and degradation.
      - Tiffany Pham

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