Despite the promise of new drugs that promote cancer cell death in people with acute myeloid leukemia, leukemia cells often take on characteristics that allow them to evade the effects of drugs within a year.
Now, new research using human tissue samples and mouse models has found that resistance in leukemia cells to a widely prescribed drug called venetoclax occurs due to a rapid increase in the breakdown and renewal of mitochondria, structures within the cell that help enhance its functions. In addition to their role in energy production, mitochondria also tell cells to die under certain adverse conditions.
This “programmed cell death” process often goes awry in cancer. Damaged mitochondria can also undergo a form of “self-consumption” called mitophagy that prevents them from sending “death signals.”
Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells evade the deadly effects of venetoclax, a drug in a class of drugs known as BH3 mimetics.
Posting in the newspaper discovery of cancer online on April 24, the researchers found that the levels of several genes associated with mitophagy were increased in 20 samples from leukemia patients compared with normal controls. The level of these genes was even higher in samples from drug-resistant leukemia patients than in non-drug-resistant leukemia patients. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which encodes a key protein in the mitochondrial outer membrane.
Other experiments with mice receiving bone marrow from patients with acute myeloid leukemia showed that the drug chloroquine, a known inhibitor of mitophagy, restored venetoclax’s ability to kill cancer cells.
“Overcoming resistance to BH3 mimetic drugs such as venetoclax is of unique clinical importance because these drugs are often used to treat people with acute myeloid leukemia,” said study co-investigative author Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine. and now an assistant professor at Rutgers University.
“Acute myeloid leukemia is notoriously difficult to treat, with less than a third of those affected living more than five years after diagnosis, so it is important to maximize the impact of existing therapies,” said the study’s co-lead investigator. , Xufeng Chen, PhD. , instructor in the NYU Grossman Department of Pathology.
“Our preclinical findings suggest that the combination of BH3 mimetics such as venetoclax with MFN2 or general mitophagy inhibitors could serve as a future therapy for acute myeloid leukemia, as current drug treatments are stalled due to drug resistance.” said the study’s principal investigator, Iannis Aifantis, PhD. .
Aifantis, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Grossman and Perlmutter, says the research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance. in people with myeloid leukemia.
Speaking of results from other studies, the researchers say they found not only that MFN2 was overly active in people with drug-resistant diseases, but also that cancer cells exposed to similar compounds that induce cell death demonstrated a doubling in the mitophagy rates.
Additional tests on cancer cells engineered to lack MFN2 showed increased sensitivity to venetoclax-like drugs compared to cells that had functional MFN2. The new study and the team’s previous research showing misshapen mitochondria in drug-resistant leukemia cells confirmed that increased mitophagy was the source of the problem.
Acute myeloid leukemia, the most common form of adult leukemia, originates in bone marrow cells and involves the rapid buildup of abnormal blood cells. Blood cancer kills more than 11,500 Americans each year. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail.
Financial support for the study was provided by National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602. Additional financial support was provided by the Leukemia & Lymphoma Society and AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments.
Aifantis has received additional research funding from AstraZeneca. This agreement is managed in accordance with the policies and practices of NYU Langone Health.
In addition to Glytsou, Chen, and Aifantis, other NYU Langone study researchers include Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos. Other co-investigators on the study include Emmanouil Zacharioudakis and Evripidis Gavathiotis, of the Albert Einstein College of Medicine in New York, who filed a patent on mitofusin inhibition based on this research; Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff, of the University of Texas MD Anderson Cancer Center at Houston; and Raoul Tibes, at AstraZeneca in Cambridge, UK.
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