Researchers have made a significant breakthrough in the treatment of acute myeloid leukemia (AML) by uncovering the mechanism behind resistance to the leukemia drug venetoclax. They discovered that cancer cells develop resistance through a process called mitophagy, where there is an increased breakdown and turnover of mitochondria. However, the inhibition of mitophagy using chloroquine was found to restore the drug’s ability to eliminate cancer cells, offering a potential therapy for AML. Future clinical trials will investigate whether the combination of chloroquine and venetoclax can effectively prevent disease recurrence.
Despite the development of new drugs to induce cancer cell death in AML patients, these cells frequently acquire resistance, rendering the drugs ineffective within a year. Recent research, utilizing human tissue samples and mouse models, has identified a surge in the breakdown and turnover of mitochondria as the cause of resistance to the widely used drug venetoclax. Mitochondria play a crucial role in energy generation and signaling programmed cell death. In cancer, this process is often disrupted, and damaged mitochondria can undergo mitophagy, a self-eating process that prevents cell death signals.
Led by scientists at NYU Langone Health and the Perlmutter Cancer Center, the study demonstrated that mitophagy enables leukemia cells to evade the effects of venetoclax, a BH3 mimetic drug. In a study published in Cancer Discovery, researchers observed increased levels of mitophagy-associated genes in leukemia patient samples compared to normal controls, with even higher levels in drug-resistant patients. Notably, the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane, exhibited heightened expression.
Further experiments using mice transplanted with bone marrow from AML patients revealed that the drug chloroquine, a known mitophagy inhibitor, restored venetoclax’s efficacy in killing cancer cells. Overcoming resistance to BH3 mimetic drugs like venetoclax is crucial in treating AML, a notoriously challenging cancer with a low survival rate. By combining BH3 mimetics with MFN2 or general mitophagy inhibitors, the researchers propose a potential future therapy for AML, as current drug treatments face limitations due to drug resistance.
The research team, led by Dr. Iannis Aifantis, plans to design a clinical trial to assess whether the combination of chloroquine and venetoclax can prevent drug resistance in individuals with AML. Additionally, the study revealed that elevated MFN2 activity was associated with drug-resistant disease, and cancer cells exposed to compounds inducing cell death demonstrated increased mitophagy rates. Cell testing further confirmed that cells lacking MFN2 exhibited greater sensitivity to venetoclax-like drugs compared to cells with functional MFN2, validating the role of increased mitophagy in drug resistance.
AML, the most prevalent form of adult leukemia, originates in bone marrow cells and involves the rapid accumulation of abnormal blood cells. Annually, this blood cancer claims the lives of over 11,500 Americans. Current treatments involve chemotherapy and a limited range of targeted drug therapies, with bone marrow transplantation considered when other options fail.
Reference: Glytsou, C., Chen, X., Zacharioudakis, E., Al-Santli, W., Zhou, H., Nadorp, B., Lee, S., Lasry, A., Sun, Z., Papaioannou, D., Cammer, M., Wang, K., Zal, T., Zal, M. A., Carter, B. Z., Ishizawa, J., Tibes, R., Tsirigos, A., Andreeff, M., Gavathiotis, E., & Aifantis, I. (2023). Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia. Cancer Discovery. DOI: 10.1158/2159-8290.CD-22-0601.
The study received funding from the National Science Foundation, additional support from the Leukemia & Lymphoma Society, and BH3 mimetic drugs from AstraZeneca. Dr. Iannis Aifantis has received additional research funding from AstraZeneca, with proper management following NYU Langone Health’s policies and practices.
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FAQ about mitophagy inhibitors
What is mitophagy and how does it relate to drug resistance in leukemia?
Mitophagy is a process where damaged mitochondria within cells are degraded and recycled. In the case of leukemia, increased mitophagy contributes to drug resistance, as it prevents the cancer cells from undergoing programmed cell death. This resistance hinders the effectiveness of drugs like venetoclax in killing leukemia cells.
How does chloroquine restore the efficacy of venetoclax in killing cancer cells?
Chloroquine is known to inhibit mitophagy, the process that enables leukemia cells to evade the effects of venetoclax. By inhibiting mitophagy, chloroquine helps to restore the ability of venetoclax to eliminate cancer cells. This combination therapy shows potential in overcoming drug resistance in acute myeloid leukemia.
What are BH3 mimetic drugs, and why are they used in treating acute myeloid leukemia?
BH3 mimetic drugs, such as venetoclax, belong to a class of medications that mimic the function of BH3-only proteins. These proteins regulate the process of programmed cell death, also known as apoptosis. BH3 mimetics like venetoclax are used in the treatment of acute myeloid leukemia to induce cancer cell death. However, drug resistance can develop over time, necessitating the need for innovative approaches to enhance their effectiveness.
How common is acute myeloid leukemia, and what are the current treatment options?
Acute myeloid leukemia (AML) is the most prevalent form of adult leukemia. It involves the rapid buildup of abnormal blood cells in the bone marrow. AML is a challenging cancer with a low survival rate, and it claims the lives of over 11,500 Americans annually. Current treatment options for AML include chemotherapy, targeted drug therapies, and bone marrow transplantation. However, drug resistance remains a significant hurdle in achieving successful outcomes.
What are the implications of this research for the future of AML treatment?
The findings of this research provide hope for the future of AML treatment. By understanding the role of mitophagy in drug resistance and the effectiveness of chloroquine in inhibiting mitophagy, a potential combination therapy with venetoclax emerges. Clinical trials will be conducted to explore the efficacy of combining chloroquine and venetoclax in preventing disease recurrence and overcoming drug resistance in AML. These findings may pave the way for improved treatment strategies and better outcomes for individuals with AML.
More about mitophagy inhibitors
- Research article on mitophagy and resistance to BH3 mimetics in acute myeloid leukemia.
- NYU Langone Health news article on the study and its implications for acute myeloid leukemia treatment.
3 comments
Wow, this is amazing research! I never knew about mitophagy and how it affects drug resistance in leukemia. This study shows that combining venetoclax with chloroquine could be a game-changer in treating acute myeloid leukemia. Can’t wait for the clinical trials to confirm these findings!
omg, mitophagy and stuff sounds complicated! But if inhibiting it with chloroquine can make venetoclax work better against cancer cells, that’s super cool! We really need better treatments for leukemia. Hope this combo therapy works in clinical trials too!
Mitochondria are fascinating! It’s wild how they play a role in cancer cell death. This study shows that targeting mitophagy with chloroquine could be a promising strategy to overcome drug resistance in acute myeloid leukemia. Can’t wait to see more research on this topic!