The study found that cancer cells can escape chemotherapy by falling asleep

Cancer cells can evade chemotherapy by entering a state similar to certain types of senescence, a type of “active hibernation” that allows them to withstand the stress induced by aggressive treatments aimed at destroying them, according to a new study by scientists at Weill Cornell Medicine. These findings have implications for the development of new drug combinations that can block senescence and make chemotherapy more effective.

In a study published on January 26 in Discovery of cancer, a journal of the American Association for Cancer Research, researchers reported that this biological process may help explain why cancers recur so often after treatment. The research was done on models of organoids and mice made from samples from patients with acute myeloid leukemia (AML). The results were also verified by observing samples from AML patients collected during treatment and recurrence.

“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, professor of Hematology and Medical Oncology for the Gebroe Family and member from Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “An old question in the field is, ‘Why can’t you get rid of all the cancer cells?’ A similar question can be asked for many other types of aggressive cancer, in addition to AML. “

For years, cancer researchers have studied how tumors are able to recover after they appear to have been completely eliminated by chemotherapy. One theory is that because not all cells in a tumor are the same at the genetic level – a condition called tumor heterogeneity – a small subset of cells is able to resist treatment and start growing again. Another theory involves the idea of ​​tumor stem cells – that some of the cells within a tumor have special properties that allow them to re-form a tumor after the application of chemotherapy.

The idea that senescence is involved does not replace these other theories. In fact, it can provide a new insight to explain these other processes, said Dr. Melnick.

In the study, the researchers found that when AML cells were exposed to chemotherapy, a subset of the cells went into hibernation, or senescence, while assuming a condition that looked a lot like inflammation. They looked like cells that have suffered an injury and need to promote healing – shutting down most of their functions while recruiting immune cells to take care of them back to health.

“These characteristics are also commonly seen in developing embryos that temporarily stop their growth due to lack of nutrition, a condition called embryonic diapause,” explained Dr. Melnick. “It is not a special process, but a normal biological activity that occurs in the context of tumors.”

Other research has revealed that this senescent inflammatory state was induced by a protein called ATR, suggesting that blocking ATR could be a way to prevent cancer cells from adopting this condition. The researchers tested this hypothesis in the laboratory and confirmed that giving leukemia cells an ATR inhibitor before chemotherapy prevented them from entering senescence, thus allowing chemotherapy to kill all cells.

It is important to note that studies published at the same time by two other groups reported that the role of senescence 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 these other studies.

Dr. Melnick and his colleagues are now working with companies that make ATR inhibitors to find a way to translate these findings into the clinic. However, much more research is needed, as many questions remain about when and how ATR inhibitors would need to be administered.

“Time will be very critical,” he said. “We still have a lot of work to do in the lab before we can study this in patients.”