Potential Therapeutic Strategy for AML Discovered in Mitophagy

Field: Medicine (Health Sciences)

acute myeloid leukemia: acute myeloid leukemiaAcute myeloid leukemia (AML) is notoriously difficult to treat. Only 28 percent of patients survive beyond 5 years after diagnosis. Mitophagy, a process in which damaged mitochondria are eliminated to prevent the transmission of death signals, has been identified as a key mechanism that allows leukemia cells to resist the effects of the widely prescribed drug venetoclax, according to a recent study published in Cancer Discovery (2023; https://doi.org/10.1158/2159-8290.CD-22-0601). Led by scientists from Perlmutter Cancer Center at NYU Langone Health, the study aimed to unravel the reasons behind the resistance of leukemia cells to venetoclax, a BH3 mimetic drug that promotes cancer cell death in individuals with AML. Despite initial positive responses to venetoclax, resistance often develops after prolonged treatment, highlighting the need for a deeper understanding of the underlying molecular mechanisms. Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now Assistant Professor at Rutgers University, along with her colleagues analyzed human tissue samples from leukemia patients and mouse models to investigate the role of mitophagy in drug resistance. They discovered that genes associated with mitophagy were significantly upregulated in leukemia patient samples, particularly in those who had developed drug resistance. The mitofusin-2 (MFN2) gene, which is a protein in the outer mitochondrial membrane, demonstrated extreme action in drug-resistant cases. To validate their findings, the researchers conducted experiments using mice that had received bone marrow transplants from AML patients. It was discovered that administering chloroquine, a known mitophagy inhibitor, restored the effectiveness of venetoclax in killing cancer cells. The findings indicate venetoclax plus MFN2 or general mitophagy inhibitors could suggest a future therapeutic strategy for AML, given that current treatments can be impeded by drug resistance. The investigators also shed light on other mechanisms contributing to drug resistance by employing loss-of-function CRISPR/Cas9 screens in human AML cells. These cells were treated with different combinations: 1) MCL1 inhibitors (MCL1i) as a monotherapy, 2) MCL1i in combination with venetoclax (MCL1i + Ven), and 3) venetoclax in combination with azacitidine (Ven + Aza). Loss of certain genes involved in mitochondrial autophagy, such as BAX, BAK1, and TP53, was found to be a common determinant of resistance. Conversely, deficiency of MFN2 and MARCH5, genes involved in mitophagy, sensitized AML cells to BH3 mimetics. Also, cancer cells exposed to compounds inducing cell death were found to have greater mitophagy rates. To gain further insights into the research, Oncology Times interviewed Glytsou as the study co-lead investigator. Oncology Times: What is the significance of BH3 mimetics in the treatment of AML? Glytsou: “For decades, the treatment options for this disease have included chemotherapy and bone marrow transplantation. However, newer therapeutics, termed BH3-mimetic drugs, are recently introduced to treat patients with AML, offering hope for clinicians and patients. BH3 mimetics have been developed to directly activate apoptosis in malignant cells, thus selectively killing leukemia cells. Unfortunately, not all AML patients respond to BH3-mimetic treatments or, in many cases, AML comes back during the therapy. Overcoming resistance to BH3 mimetics drugs is of unique clinical significance because these medications are now on the frontline of treating people with acute myeloid leukemia.” Oncology Times: What are the molecular mechanisms underlying resistance to BH3 mimetics in AML? Glytsou: “To understand the cellular mechanisms of resistance to BH3 mimetics in AML, we performed unbiased genome-wide CRISPR screens in AML cell lines. In other words, we deleted every single gene in the cancer cells and we pinpointed those genes that, when absent, make the cells more sensitive to BH3 mimetics. Interestingly, we found that the loss of genes involved in mitochondrial dynamics and mitophagy sensitizes AML cells to BH3-mimetics combinations. In addition, we examined AML patient samples that were resistant to BH3 mimetics treatment, and we showed they are characterized by high mitophagy rates compared to sensitive AML samples. “Mitophagy is a type of autophagy, which is a ‘self-eating’ process inside the cell. With autophagy, cells can eliminate and recycle various damaged cellular components, like proteins or whole organelles such as mitochondria. The specific process of self-eating mitochondria is called mitophagy. We believe that with excessive mitophagy, cancer cells can eliminate mitochondrial damage, maintain a healthy mitochondrial population, and hence escape the pathway of programmed cell death. Importantly, we also showed that novel compounds that block mitophagy can enhance the efficacy of BH3 mimetics in various AML models and can reverse drug resistance.” Oncology Times: What are the potential clinical implications of targeting mitophagy and mitochondrial quality control mechanisms in AML treatment with BH3 mimetics? Glytsou: “Drug resistance is one of the main challenges for successful cancer treatment. Our recent findings shed light on the molecular mechanisms that govern resistance and will help design more effective combinatorial therapies for AML in the future. “Specifically, our study proposed that blocking mitophagy using novel specific compounds that target MFN2—a mitophagy enabler—or other broader autophagy inhibitors like chloroquine can enhance the efficacy of BH3 mimetics and can reverse drug resistance in preclinical models of AML. These findings can be the basis for near-future clinical trials for AML. Overall, we aim to replace chemotherapy and transplantation, which can have painful or dangerous side effects, and instead use innovative therapeutic strategies to increase the patient's survival. Future clinical trials are necessary to determine whether combining BH3 mimetics with general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia, especially for patients who do not respond to these targeted treatments. “Noteworthy, BH3 mimetics are used in clinics for the treatment of other hematologic malignancies as well, including chronic lymphocytic leukemia and small lymphocytic lymphoma. Moreover, various BH3 mimetics are in clinical trials for the treatment of other types of blood malignancies as well as solid tumors. Future preclinical and clinical studies will reveal if our proposed drug combination is effective against other cancers, too.” Dibash Kumar Das is a contributing writer.