Study finds that cancer cells can avoid chemotherapy by becoming dormant

Cancer cells can evade chemotherapy by entering a state that is consistent with certain types of aging, a type of “active hibernation” that enables them to withstand the stress caused by aggressive treatments aimed at to destroy, according to a new study by scientists from Weill. Cornell medicine. These findings have implications for the development of new drug combinations that may block aging and make chemotherapy more effective.

In a study published on January 26 in Cancer discovery, a journal of the American Society for Cancer Research, the researchers reported that this biological process can help explain why cancer occurs so frequently after treatment. The research was done in both organoid and mouse models made from samples from patients of acute myeloid leukemia (AML) tumors. The findings were also verified by looking at samples from AML patients collected during the course of treatment and relapse.

“Acute myeloid leukemia can be put into remission with chemotherapy, but it almost always comes back, and when it does, it is incurable,” said senior author Dr. Ari M. Melnick, the professor of hematology and medical oncology at Gebroe, said and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. An early question in the field was, ‘Why can’t you get rid of all the cancer cells?’ A similar question can be asked in addition to AML for many other types of aggressive cancer. “

For years, cancer researchers have studied how tumors can recover after being completely eradicated by chemotherapy. One theory was that because not all cells within a tumor are genetically the same – a condition called the heterogeneity of the tumor – that a small subset of cells can withstand treatment and begin to grow again. Another theory involves the idea of ​​tumor stem cells – that some cells within a tumor have special properties that enable them to form a tumor after chemotherapy has been given.

The idea that aging is involved does not replace these other theories. In fact, it may provide new insight into the explanation of these other processes, said dr. Melnick said.

In the study, the researchers found that when AML cells were exposed to chemotherapy, a subset of the cells went into hibernation or aging, while at the same time accepting a condition that looked very much like inflammation. They look similar to cells that are injured and need to promote wound healing – while most of their functions are stopped while immune cells are recruited to heal them.

“These traits are also commonly seen in the development of embryos that temporarily stop their growth due to a lack of nutrition, a condition called embryonic diapause,” said Dr. Melnick explains. “It’s not a special process, but normal biological activity that takes place in the context of crops.”

Further research has revealed that this inflammatory aging condition is induced by a protein called ATR, suggesting that blocking ATR may be a way to prevent cancer cells from contracting this condition. The investigators tested this hypothesis in the laboratory and confirmed that giving leukemia cells is an ATR inhibitor before chemotherapy prevents them from entering aging so that chemotherapy can kill all the cells.

Importantly, studies published simultaneously from two other groups reported that the role of aging is important not only for AML but also for recurrent cases of breast cancer, prostate cancer, and gastrointestinal cancer. Dr. Melnick contributed to one of the other studies.

Dr. Melnick and his colleagues are working closely with companies that make ATR inhibitors to find a way to translate these findings to the clinic. However, much more research is needed as there are still many questions about when and how ATR inhibitors should be given.

“Timing will be very critical,” he said. “We still have a lot of practice in the lab before we can study it in patients.”