A research team at Oregon Health & Science University has discovered a promising new drug combination that may help people with acute myeloid leukemia (AML) overcome resistance to one of the most common frontline therapies.
The scientists analyzed more than 300 AML patient samples and found that pairing venetoclax (ven), a standard AML drug, with palbociclib (palbo), a cell-cycle inhibitor currently approved for breast cancer, produced significantly stronger and more durable anti-leukemia activity than venetoclax alone. The findings were confirmed in human tissue samples, as well as in mouse models carrying human leukemia cells. Studies suggested that the combination therapy co-targets cell cycle and protein synthesis pathways and mitigates resistance mechanisms observed with single agent venetoclax or palbociclib.
“Of the 25 drug combinations tested, venetoclax plus palbociclib was the most effective. That really motivated us to dig deeper into why it works so well—and why it appears to overcome resistance seen with current therapy,” said Melissa Stewart, PhD, research assistant professor at OHSU and lead author of the study. Stewart is first author of the team’s published paper in Cell Reports Medicine, titled “CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.”
More than 20,000 Americans are diagnosed with AML each year, making it one of the most common types of leukemia—and one of the most aggressive. Since its approval by FDA in 2019, the BCL2 inhibitor venetoclax combined with the hypomethylating agent azacitidine has become a go-to treatment for many people with AML. But resistance remains a nearly universal problem. “… drug resistance and disease relapse continue to be major hurdles in the long-term management and overall survival of patients with AML due to the heterogeneity of genetic lesions and tumor cell differentiation states that affect how tumor cells respond to a given drug regimen,” the authors wrote.
“Unfortunately, almost everyone will eventually have drug resistance,” said the study’s corresponding author, Jeffrey Tyner, PhD, professor of cell, developmental and cancer biology in the OHSU School of Medicine. “This regimen has improved initial response rates and quality of life, but the five-year survival rate for AML is still only about 25% to 40%. We have a lot of work to do.”
For their newly reported study the team used ex vivo drug sensitivity assays to analyze 302 AML patient samples, assessing 25 drugs in combination with venetoclax. They identified venetoclax plus the cyclin dependent kinase (CDK)4/6 inhibitor palbociclib to be one of the most “potent and efficacious” combinations. Palbociclib is approved by FDA for the treatment of hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. “The use of CDK4/6 inhibitors in hematological malignancies has not been studied in detail,” the team noted.
The study found that AML cells exposed to venetoclax alone try to adapt by increasing protein production, a shift that helps them survive. Adding palbociclib blocked this adaptation by regulating protein-production machinery inside the cell. “Patient samples that responded strongly to the combination showed clear downregulation of genes involved in protein synthesis,” Stewart said. “This was a big clue.”
A genome-wide CRISPR screen revealed that while venetoclax alone becomes more effective when protein-production genes are lost, the combination therapy does not rely on that same vulnerability—a sign the two drugs work together to shut down multiple survival pathways.
“Our CRISPR screen showed that RB1 and other cell cycle genes conferred resistance to palbo,” the investigators further reported. “Interestingly, while loss of BAX and RB1 conferred resistance to the single agent ven or palbo, respectively, the ven+palbo combination was unaffected by the loss of either gene, suggesting that the presence of both drugs may mitigate these clinically relevant resistance mechanisms that occur in the context of single-agent exposures.”
The research team tested the combination using mouse models implanted with human AML cells carrying mutations known to cause venetoclax resistance. “In this model, venetoclax alone didn’t extend survival at all—just as we’d expect based on the genetics,” Stewart said. “But with the combination, the majority of mice lived 11 to 12 months. In fact, one mouse was still alive when the study ended.” In their paper the team further noted, “Taken together, these data show that the effectiveness of ven+palbo translates from our ex vivo drug assays into an in vivo disease model.”
Mutations in IKZF1 occur in about 3-5% of AML patients and are associated with poor treatment responses and reduced overall survival. The team’s study results also indicated that this subpopulation of patients would likely not benefit from the venetoclax plus palbociclib combination. “While the ven+palbo combination appeared to mitigate common resistance mechanisms of BAX or RB1 loss, the CRISPR screen showed that loss of IZKF1, a transcription factor involved in myeloid and lymphoid differentiation, conferred resistance to both palbo and the combination,” they acknowledged. “We found that loss of IKZF1 leads to upregulation of the AXL receptor, the overexpression of which leads to resistance to various targeted therapies.” Further studies indicated that targeting AXL might be effective in IKZF1-mutated AML. Their findings, they noted, “… suggest that AXL inhibitors, as single agents, may represent an effective strategy to mitigate IKZF1-mediated resistance to ven and ven+palbo.”
In summary, they wrote, “… our findings establish ven+palbo as a promising drug regimen and provide further insight into which subpopulations of patients with AML are most likely to benefit from the combination, specifically patients with monocytic disease, as well as patients lacking IKZF1 mutations or harboring acquired RB1 or BAX mutations … We demonstrated that AXL inhibitors retained their effectiveness with loss of IKZF1, suggesting a potential treatment strategy warranting further investigation for this hard-to-treat subpopulation.”
Tyner, a co-leader of the national Beat AML 1.0 program, said the new study builds directly on the work of that national initiative to help transform and expand treatments for AML. “This combination was nominated from the Beat AML data, and Dr. Stewart validated that prediction, showing not only that it works, but why,” Tyner said.
Stewart says the project holds personal significance. “I’m a breast cancer survivor and was treated here at OHSU, so 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. Working on AML gave me a way to contribute.”
The researchers emphasized the importance of following scientific data even when it leads outside traditional boundaries. “Some might ask why a breast cancer drug would work in AML,” Tyner said. “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.”
Stewart said that the team is already evaluating other drugs similar to palbociclib—many of them also approved for breast cancer—to expand future clinical trial options. The researchers hope to move the combination toward clinical testing.
“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 said. “Making it a clinical reality will take work, but this is exactly why we do what we do.”
