New Delhi: Some cancer cells turn on their “cell death” programme during drug therapy. Instead of killing them, the therapy helps them persist and regrow in some cases. A new study by the University of California, San Diego, has discovered this phenomenon and explained how drug resistance in cancer cells functions. By targeting this cell-death programme in cancer cells, scientists could potentially stop the regrowth of cancer after therapy.
The US researchers described this phenomenon of cancer drug resistance in their paper in the peer-reviewed journal Nature Cell Biology, published last month.
As a disease that causes 10 million deaths globally every year, cancer is a global threat, and one of the main factors in many forms of cancer is the regrowth of tumours. Doctors often note it as “cancer relapse” or remission, and it happens when cancer cells don’t get fully destroyed during the first treatment, and regrow after a period of time.
Cancer relapse depends on the type of cancer—some have higher relapse rates, like lung cancer, while others, like breast cancer, have a lower rate—but there are multiple causes for relapse. One of the main ones is drug resistance, where, just like bacteria and other microbes, cancer cells develop resistance to medicines.
In their study, the researchers wanted to see if they could identify early signs of drug resistance in some cancer cells. However, instead of finding signs of microbial or genomic changes in the cells, they noticed that some cells responded to cancer therapy by becoming “persister cells” through specific “enzyme” functions.
During drug therapy, like all cancer cells, the persisting cells also experience growth arrest. This means they stop growing and are dormant. After that, these cells activate their cell-death programme, which is the body’s way of dismantling dying cells, but it doesn’t kill them entirely. Instead, what this cell-death programme does is release some enzymes that help these cells escape growth arrest and start to regrow.
These enzymes are called DNA Fragmentation Factor B (DFFB) and are used by the body to fragment the DNA in dead cells. But DFFB in these cancer cells is activated to “sublethal levels”, which means it won’t kill the cell but will allow it to escape the growth arrest caused by the anti-cancer drug.
“This flips our understanding of cancer cell death on its head,” said senior author Matthew J. Hangauer, assistant professor of dermatology at University of California’s San Diego School of Medicine, in a communication.
“Cancer cells which survive initial drug treatment experience sublethal cell death signalling which, instead of killing the cell, actually helps the cancer regrow.”
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What this means for cancer therapy
The study is fundamental in understanding the different ways in which cancer cells can develop drug resistance. In this case, instead of changing their genetic make-up or responding to specific types of anti-cancer drugs, the cancer cells just use an internal cell mechanism to evade drugs and persist in the body.
More importantly, by exposing how cancer cells can survive in the body using specific enzymes, the study provides a possible pathway for future cancer therapy to target.
The researchers state that if scientists are able to figure out how to block this apoptosis machinery (cell-death programme), then they might be able to stop cancer resistance before it even begins.
In fact, the researchers tried doing this in an experimental setup. They disabled DFFB in models of melanoma, lung cancer and breast cancer, and found that the cancer cells could no longer break out of their growth arrest phase. They remained dormant cells and did not increase the threat of relapsing cancer.
This DFFB mechanism, the study added, was not essential in normal cells, so they could dismantle it without leading to major side effects, too.
“Most research on resistance focuses on genetic mutations,” said August F. Williams, first author of the study.
“Our work shows that non‑genetic regrowth mechanisms can come into play much earlier, and they may be targetable with drugs. This approach could help patients stay in remission longer and reduce the risk of recurrence.”
(Edited by Nida Fatima Siddiqui)
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