How do cancer cells evade the effects of chemotherapy? Results from a study by scientists at Weill Cornell Medicine in New York City, NY, and published Cancer Discovery, a publication of the American Association for Cancer Research (AACR), demonstrate that cancer cells can dodge chemotherapy by entering a state that bears similarity to certain kinds of senescence, a state in which cells stop dividing and slip into a state of growth arrest without the cells dying, a type of “active hibernation” that enables them to weather the stress induced by aggressive treatments aimed at destroying them.

The findings have implications for developing new drug combinations that could block senescence and make chemotherapy more effective.

Ari M. Melnick, MD, at the Joan and Sanford I. Weill Department of Medicine/Pharmacology; Director, Sackler Center for Biomedical and Physical Sciences Laurel Gebroe Family Professor of Hematology/Oncology in Honor of Morton Coleman, M.D, Weill Cornell Medicine focuses his research on the biology of the immune system, lymphomas, and leukemias, epigenetics, and cancer experimental therapeutics. Photo courtesy: © 2015 – 2021 Cornell Research/Patricia Kuharic

Recurring after treatment
The study authors reported that this biological 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 investigators also verified their findings by looking at samples from AML patients that were collected throughout the course of treatment and relapse.[1]

The choice for AML was based on the fact that AML patients frequently relapse after chemotherapy, and yet, the mechanism by which AML reemerges is not fully understood.

“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 Ari M. Melnick, MD, the Gebroe Family Professor of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

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“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,” Melnick noted.

Tumor heterogeneity
For many 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. In essence, tumor heterogeneity suggests that different tumour cells can show distinct morphological and phenotypic profiles (phenomenon occurs both between tumors (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity).

Another theory involves the idea of tumor or cancer stem cells (CSC)–that some of the cells within a tumor have special properties that allow them to re-form a tumor after chemotherapy has been given. These Cancer stem cells comprise the subpopulation of tumor bulk and acquire resistant to conventional therapies and are considered as the primary tumor initiator cells.[2]

“The idea that senescence is involved does not replace these other theories. In fact, it could provide new insight into explaining these other processes,” Melnick observed.

Hibernation
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,” Melnick explained.

“It’s not a special process, but normal biological activity that’s playing out in the context of tumors,” he added.

ATR
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.

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,” Melnick said. “We still have a lot to work out in the laboratory before we can study this in patients.”

Study disclosures
Cihangir Duy, MD, a former postdoctoral fellow in Melnick’s lab, was the study’s first author. Duy now leads his own lab at Fox Chase Cancer Center in Philadelphia. Melnick has been a paid consultant for KDAC Therapeutics, Epizyme, and Constellation Pharmaceuticals.

Reference
[1] Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman FE, Lee TC, Chin CR, Durmaz C, Kawabata KC, Dhimolea E, Mitsiades CS, Doehner H, D’Andrea RJ, Becker MW, Paietta EM, Mason CE, Carroll M, Melnick AM. Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence. Cancer Discov. 2021 Jan 26:candisc.1375.2020. doi: 10.1158/2159-8290.CD-20-1375. Epub ahead of print. PMID: 33500244.[Article]
[2] Kuşoğlu A, Biray Avcı Ç. Cancer stem cells: A brief review of the current status. Gene. 2019 Jan 10;681:80-85. doi: 10.1016/j.gene.2018.09.052. Epub 2018 Sep 27. PMID: 30268439.
[3] Eun K, Ham SW, Kim H. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep. 2017 Mar;50(3):117-125. doi: 10.5483/bmbrep.2017.50.3.222. PMID: 27998397; PMCID: PMC5422023.

Featured image: Photomicrograph of bone marrow aspirate from a patient with leukocytosis, showing blast cells of acute myeloid leukemia. Photo courtesy: © 2015 – 2021 Cornell Research/Shutterstock.

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