Cancer cells can dodge chemotherapy by entering a state that bears
similarity to certain kinds of senescence, a type of "active hibernation"
that enables them to weather 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 developing new drug
combinations that could block senescence and make chemotherapy more
effective.
In a study published Jan. 26 in Cancer Discovery, a journal of the American
Association for Cancer Research, the investigators reported that this
biologic process could help explain why cancers so often recur after
treatment. The research was done in both organoids and mouse models made
from patients' samples of acute myeloid leukemia (AML) tumors. The findings
were also verified by looking at samples from AML patients that were
collected throughout 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's incurable," said senior
author Dr. Ari M. Melnick, the Gebroe Family Professor of Hematology and
Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center
at Weill Cornell Medicine. "A longstanding question in the field has been,
'Why can't you get rid of all the cancer cells?' A similar question can be
posed for many other types of aggressive cancer in addition to AML."
For years, cancer researchers have studied how tumors are able to rebound
after they appear to be completely wiped out by chemotherapy. One theory has
been that because not all cells within a tumor are the same at the genetic
level--a condition called tumor heterogeneity--a small subset of cells are
able to resist treatment and begin 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 chemotherapy has
been given.
The idea that senescence is involved does not replace these other theories.
In fact, it could provide new insight into explaining these other processes,
Dr. Melnick said.
In the study, the researchers found that when AML cells were exposed to
chemotherapy, a subset of the cells went into a state of hibernation, or
senescence, while at the same time assuming a condition that looked very
much like inflammation. They looked similar to cells that have undergone an
injury and need to promote wound healing--shutting down the majority of
their functions while recruiting immune cells to nurse them back to health.
"These characteristics are also commonly seen in developing embryos that
temporarily shut down their growth due to lack of nutrition, a state called
embryonic diapause," Dr. Melnick explained. "It's not a special process, but
normal biological activity that's playing out in the context of tumors."
Further research revealed that this inflammatory senescent 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 investigators tested
this hypothesis in the lab and confirmed that giving leukemia cells an ATR
inhibitor before chemotherapy prevented them from entering senescence,
thereby allowing chemotherapy to kill all of the cells.
Importantly, studies published at the same time from two other groups
reported that the role of senescence is important not just for AML, but for
recurrent cases of breast cancer, prostate cancer and gastrointestinal
cancers as well. Dr. Melnick was a contributor to one of those other
studies.
Dr. Melnick and his colleagues are now working with companies that make ATR
inhibitors to find a way to translate these findings to the clinic. However,
much more research is needed, because many questions remain about when and
how ATR inhibitors would need to be given.
"Timing will be very critical," he said. "We still have a lot to work out in
the laboratory before we can study this in patients."
Reference:
Duy C, Li M, Teater M, et al. Chemotherapy induces senescence-like resilient
cells capable of initiating AML recurrence. Cancer Discov. 2021. doi:
10.1158/2159-8290.CD-20-1375
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