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Research Into Reactive Oxygen Species Could Help Address AML Treatment Resistance

Treatment resistance remains a major challenge in the treatment of acute myeloid leukemia (AML), and leveraging actionable therapeutic targets is far from straightforward.

Reactive oxygen species (ROS) appear to play a key role in treatment resistance among patients with acute myeloid leukemia (AML). Yet, a new review explains that the precise role ROS plays is complex, and leveraging ROS into actionable therapeutic targets is far from straightforward. The findings were published in the journal Cancer Drug Resistance.

The investigators began by outlining the challenge of treatment resistance in AML. The complete remission rate for patients with AML undergoing standard induction therapy varies from about 40% to more than 90%, depending on characteristics such as patient age and genetic characteristics, they explained.

“However, at least 50% of younger patients and 80% of those older than 60 years will experience relapse within 5 years,” they noted, adding that even with additional chemotherapy or hematopoietic stem cell transplant, most patients will not survive 5 years. “In most cases, it has been shown that the founder leukemic clone persisted following chemotherapy and established the basis of relapse years later.”

Thus, much of the recent research into AML has been focused on investigating leukemic stem cells (LCS) as the source of relapse, the authors said. Those cells rely on oxidative phosphorylation (OXPHOS) for energy. Venetoclax (Venclexta; Abbvie/Genentech), a selective BCL-2 inhibitor, suppresses OXPHOS, the authors noted, adding to the drug’s antileukemic activity. Yet, they said, the effect has its limits.

AML representation | Image credti: Andrey - stock.adobe.com.

AML representation | Image credti: Andrey - stock.adobe.com.

“Despite promising responses in various studies, resistance to VEN-based combinations can emerge in AML patients,” the authors said. Previous research has indicated that the majority of patients who initially responded to venetoclax-combination therapy relapsed within about a year, Tonks and colleagues said.

The understanding of the role of OXPHOS has led to increased investigation of ROS, which are byproducts of OXPHOS. However, the investigators said ROS appears to affect AML resistance in multiple ways.

“The contribution of ROS to drug resistance is thought to be influenced by its concentration, the underlying source of production, or the type of treatment, and therefore, it is complex,” they wrote. In terms of concentration, both high and low levels of ROS can play a role in therapy resistance and relapse.

“Lower levels of ROS are associated with the maintenance of leukemia stemness, reduced sensitivity to chemotherapy, and a higher risk of future relapse,” the authors explained. “In contrast, NOX2-mediated ROS generation may enhance AML cell survival by providing an additional source of energy. This occurs through mediating the transfer of mitochondria and essential metabolites from stromal cells in the microenvironment to AML cells.”

NOX2-generated ROS may induce metabolic alterations in AML cells, lending protection against chemotherapy and potentially altering the microenvironment to suppress immune components.

As the contribution of ROS to AML treatment resistance is complex, so too is the challenge of directly targeting ROS. On the other hand, targeting NOX2 shows promise.

“Recent increasing evidence highlights the significance of NOX2 in therapy resistance,” the authors wrote. “Preliminary data even suggest a predictive role for NOX2 expression in resistance to therapy.”

The authors said there are a number of NOX2 inhibitors already available, which ought to be the subject of future investigation as potential therapeutic options.

“Alternatively, conducting a detailed analysis of the signaling pathways altered by ROS and exploring them as potential therapeutic targets, rather than directly targeting ROS or their substrates, offers alternative avenues for research in the development of additional therapeutic targets in AML,” they concluded.

Reference

Khorashad JS, Rizzo S, Tonks A. Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia. Cancer Drug Resist. 2024;7:5. Published 2024 Feb 22. doi:10.20517/cdr.2023.125

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