A research team at Oregon Health & Science University has identified a promising drug combination that could help patients with acute myeloid leukemia (AML) overcome resistance to standard treatments. The study, published in Cell Reports Medicine, highlights the effectiveness of combining venetoclax, a widely used AML medication, with palbociclib, a cell-cycle inhibitor typically used in breast cancer therapy.
The researchers analyzed samples from over 300 AML patients and discovered that the combination therapy produced significantly stronger and more durable anti-leukemia effects compared to venetoclax alone. This finding was further validated using human tissue samples and mouse models implanted with human leukemia cells.
Understanding the Challenge of Drug Resistance
Since its approval by the Food and Drug Administration in 2019, venetoclax, when paired with azacitidine, has become a preferred treatment for many AML patients. Despite this progress, drug resistance remains a significant hurdle. According to Jeffrey Tyner, Ph.D., a professor of cell, developmental and cancer biology at OHSU, nearly all patients will eventually experience this resistance. Although the current regimen has improved initial response rates and quality of life, the five-year survival rate for AML patients remains low, estimated at only 25% to 40%.
Tyner, who co-leads the national Beat AML 1.0 program, emphasized that the recent findings build on this initiative’s goal of enhancing AML treatments. “This combination was nominated from the Beat AML data, and Dr. Stewart validated that prediction,” he said. The study revealed that AML cells tend to increase protein production in response to venetoclax alone, a mechanism that enables their survival. Introducing palbociclib disrupted this adaptation, affecting the cell’s protein-production machinery.
Key Findings and Future Directions
The research team observed that patient samples responding well to the combination therapy showed a clear downregulation of genes linked to protein synthesis. “This was a big clue,” stated Melissa Stewart, Ph.D., the study’s lead author. A genome-wide CRISPR screen indicated that while venetoclax becomes more effective in the absence of specific protein-production genes, the combination therapy does not rely on that vulnerability. This suggests that the two drugs function together to inhibit multiple survival pathways.
In experiments using mouse models with human AML cells known to resist venetoclax, the results were striking. “In this model, venetoclax alone didn’t extend survival at all—just as we’d expect based on the genetics,” Stewart explained. “But with the combination, the majority of mice lived between 11 to 12 months.” Remarkably, one mouse remained alive when the study concluded.
Stewart expressed a personal connection to the research, noting her experience as a breast cancer survivor treated at OHSU. “I know what it’s like to be a cancer patient,” she said. “The hope that research and clinical trials can bring—that’s what motivates me.”
Both researchers highlighted the importance of exploring scientific data beyond traditional boundaries. Tyner remarked, “Some might ask why a breast cancer drug would work in AML. But biology can be shared across very different cancers.” This underscores the significance of maintaining an open mind in research.
Looking ahead, the team is evaluating other drugs similar to palbociclib, many of which are also approved for breast cancer, to broaden future clinical trial options. “We haven’t tested it in patients yet, but based on everything we’ve seen, our prediction is that this combination would mitigate most known resistance mechanisms to the current standard therapy,” Tyner noted. He added, “Making it a clinical reality will take work, but this is exactly why we do what we do.”
The ongoing research aims to transition the combination therapy into clinical testing, with the hope of providing new avenues for treating AML and improving outcomes for patients battling this aggressive form of leukemia.
