A research team at Oregon Health & Science University has made significant strides in treating acute myeloid leukemia (AML) through a new drug combination. Their study reveals that pairing venetoclax, a standard treatment for AML, with palbociclib, a cell-cycle inhibitor approved for breast cancer, shows promise in overcoming resistance to conventional therapies.
Published in Cell Reports Medicine, the research analyzed over 300 patient samples diagnosed with AML. The findings indicated that the combination of venetoclax and palbociclib produced markedly stronger and more durable anti-leukemia effects compared to venetoclax alone. The effectiveness was corroborated in both human tissue samples and mouse models infused with human leukemia cells.
“Of the 25 drug combinations tested, venetoclax plus palbociclib was the most effective,” said Melissa Stewart, Ph.D., the study’s lead author. This discovery prompted further investigation into the underlying mechanisms that allow this combination to overcome resistance often encountered in AML treatments.
Every year, more than 20,000 Americans receive an AML diagnosis, making it one of the most prevalent types of leukemia. One of the major hurdles in effective treatment is drug resistance. According to Jeffrey Tyner, Ph.D., corresponding author of the study, “Unfortunately, almost everyone will eventually have drug resistance.” Although the combination of venetoclax and azacitidine has improved initial response rates since its FDA approval in 2019, the five-year survival rate for AML remains dismal, ranging from 25% to 40%.
The research builds on the national Beat AML 1.0 program, which aims to enhance AML treatments. Tyner noted that the new combination was nominated based on data from this initiative, and Stewart validated its effectiveness.
The study revealed that AML cells exposed solely to venetoclax attempt to adapt by increasing protein production, which aids their survival. Introducing palbociclib disrupted this adaptive response by regulating the cellular machinery responsible for protein production. “Patient samples that responded strongly to the combination showed clear downregulation of genes involved in protein synthesis,” Stewart explained.
A genome-wide CRISPR screen demonstrated that while venetoclax’s efficacy increases when protein-production genes are lost, the combination therapy does not rely on this vulnerability. This indicates that the two drugs work synergistically to inhibit multiple survival pathways.
In mouse models implanted with human AML cells featuring mutations known to cause venetoclax resistance, the combination therapy yielded impressive results. “In this model, venetoclax alone didn’t extend survival at all—just as we’d expect based on the genetics,” Stewart stated. “But with the combination, the majority of mice lived 11 to 12 months. In fact, one mouse was still alive when the study concluded.”
The research holds personal significance for Stewart, a breast cancer survivor treated at OHSU. “The hope that research and clinical trials can bring—that’s what motivates me,” she remarked. “Working on AML gave me a way to contribute.”
Both researchers emphasized the importance of remaining open to unexpected findings. “Some might ask why a breast cancer drug would work in AML,” Tyner noted. “But biology can be shared across very different cancers. This is a great example of why keeping an open mind matters and following the data where it leads.”
The research team is already exploring other drugs similar to palbociclib, many of which are also approved for breast cancer, to broaden future clinical trial options. Tyner expressed optimism about the potential of this combination therapy: “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.”
As the team prepares for clinical testing, they remain focused on transforming their findings into a viable treatment option for AML patients. “Making it a clinical reality will take work, but this is exactly why we do what we do,” Tyner concluded.
