A research team at Oregon Health & Science University has identified a promising drug combination that may enhance treatment options for patients with acute myeloid leukemia (AML). The study, published in Cell Reports Medicine, highlights the effectiveness of combining venetoclax, a standard AML therapy, with palbociclib, an inhibitor approved for breast cancer. This combination showed significantly improved anti-leukemia activity in over 300 patient samples compared to venetoclax used alone.
The research demonstrated that the pairing of these two drugs produced stronger and more lasting results. The findings were validated through tests on human tissue samples as well as in mouse models implanted with human leukemia cells. “Of the 25 drug combinations tested, venetoclax plus palbociclib was the most effective,” stated Melissa Stewart, Ph.D., the study’s lead author. “This motivated us to explore why it works so well and how it can overcome resistance.”
With more than 20,000 Americans diagnosed with AML annually, this research addresses a pressing need for effective treatments. Despite the advancements made since venetoclax was approved by the Food and Drug Administration in 2019, drug resistance remains a significant hurdle in AML therapy. According to Jeffrey Tyner, Ph.D., a corresponding author of the study, “Almost everyone will eventually experience drug resistance. The five-year survival rate for AML is still only about 25% to 40%.”
The study builds on the national Beat AML 1.0 program, which aims to enhance treatment strategies for AML. Tyner noted that the combination of venetoclax and palbociclib emerged from the program’s data, confirming its potential effectiveness.
Research insights indicate that AML cells treated with venetoclax alone attempt to adapt by increasing protein production, which aids their survival. Introducing palbociclib disrupts this adaptation through its regulation of cellular machinery responsible for protein synthesis. “Patient samples that responded strongly to the combination exhibited downregulation of genes involved in protein synthesis,” said Stewart, pointing to crucial findings that explain the drug pairing’s success.
A genome-wide CRISPR screen further revealed that while venetoclax becomes more effective when certain protein-production genes are lost, the combination therapy does not depend on that vulnerability. This indicates that the two drugs collaborate to shut down multiple survival pathways in cancer cells.
The research team also tested this combination using mouse models with human AML cells that carry mutations known to cause venetoclax resistance. In these tests, venetoclax alone did not extend survival. However, the combination therapy resulted in the majority of mice living for 11 to 12 months, with one mouse still alive at the conclusion of the study.
Stewart shared a personal connection to the research, highlighting her experience as a breast cancer survivor treated at OHSU. “The hope that research and clinical trials can bring motivates me,” she said. “Working on AML gives me a way to contribute to this fight.”
Both researchers emphasized the importance of pursuing scientific data that can lead to unconventional solutions. Tyner remarked, “Some may question why a breast cancer drug would be effective in AML, but biology can be shared across different cancers. This underscores the value of keeping an open mind.”
Looking ahead, Stewart mentioned that the team is 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 their findings, stating, “We haven’t tested it in patients yet, but based on what we’ve seen, we predict this combination could mitigate most known resistance mechanisms to current therapies. Turning this into a clinical reality will require effort, but this is precisely why we conduct research.”
The study, titled “CDK4/6 Inhibition Overcomes Venetoclax Resistance Mechanisms with Enhanced Combination Activity in Acute Myeloid Leukemia,” represents a significant step forward in the fight against this aggressive form of leukemia.
