OHSU researchers find breast cancer drug boosts leukemia treatment

A research team at Oregon Health & Science University has discovered a promising new drug combination that may help people with acute myeloid leukemia overcome resistance to one of the most common frontline therapies.

In a study published today in Cell Reports Medicine, researchers analyzed more than 300 acute myeloid leukemia, or AML, patient samples and found that pairing venetoclax, a standard AML drug, with palbociclib, 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.

“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, Ph.D., research assistant professor at OHSU and lead author of the study.

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.

A major challenge: drug resistance

Since the drug was approved by the Food and Drug Administration in 2019, venetoclax combined with azacitidine has rapidly become a go-to treatment for many people with AML. But resistance remains a nearly universal problem.

“Unfortunately, almost everyone will eventually have drug resistance,” said the study’s corresponding author, Jeffrey Tyner, Ph.D., 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.”

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.

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, a drug approved for breast cancer, 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 also 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.

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.”

A personal connection, following the data

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.”

Both 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.”

In addition to Stewart and Tyner, other OHSU coauthors on this study include Jessica Gibbs, B.S., Kevin Watanabe-Smith, Ph.D., Ariel Nguyen, M.S., Isabel Kenna, B.A., Karina Thiel-Klare, B.S., Andy Kaempf, M.S., Daniel Bottomly, M.S., Stephen Kurtz, Ph.D., Christopher A. Eide, B.A., Nicola Long, B.A., Jennifer N. Saultz, D.O., Luca Sax, B.S., Ariane Huang, B.S., Shannon K. McWeeney, Ph.D., and Bill H. Chang, M.D., Ph.D.

This study was supported by the National Cancer Institute, of the National Institutes of Health, under Award numbers U54CA224019 and R01CA262758; as well as the Waldman Family Fund for AML Research, the George Ettelson Endowed Professorship in Acute Myeloid Leukemia Research, the Mark Foundation for Cancer Research, the Silver Family Foundation, and the Marsha and Richard Wright Sr Family Endowed Professorship of Pediatric Oncology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. The authors thank all the patients for the generous use of their samples and thank the Massively Parallel Sequencing Shared Resource for Illumina sequencing support and the flow cytometry core at OHSU.

All research involving animal subjects at OHSU must be reviewed and approved by the university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.