Combination therapy offers hope for AML patients facing drug resistance

Combination therapy offers hope for AML patients facing drug resistance

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

In a study published today inCell Reports MedicineResearchers analyzed more than 300 patient samples with acute myeloid leukemia (AML) and found that combining 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 results 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 the 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 and aggressive forms of leukemia.

A major challenge: drug resistance

Since the drug was approved by the Food and Drug Administration in 2019, venetoclax in combination with azacitidine has quickly become the treatment of choice for many people with AML. But resistance remains an almost universal problem.

“Unfortunately, almost everyone will have drug resistance at some point,” said study corresponding author Jeffrey Tyner, Ph.D., professor of cell, developmental and cancer biology at 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 to do.”

Jeffrey Tyner, School of Medicine, OHSU

Tyner, a co-leader of the national Beat AML 1.0 program, said the new study builds directly on the work of this national initiative to transform and expand treatment for AML.

“This combination was nominated based on the Beat AML data and Dr. Stewart confirmed this prediction, showing not only that it works, but why,” Tyner said.

The study found that AML cells exposed to venetoclax alone attempt to adapt by increasing protein production, a change that helps them survive. The addition of palbociclib, a drug approved for breast cancer, blocked this adaptation by regulating the protein production machinery within the cell.

“Patient samples that responded strongly to the combination showed significant downregulation of genes involved in protein synthesis,” Stewart said. “That was a big clue.”

A genome-wide CRISPR screen also found that while venetoclax alone becomes more effective when protein production genes are lost, the combination therapy does not rely on the same susceptibility - a sign that the two drugs work together to disrupt multiple survival pathways.

The research team tested the combination using mouse models implanted with human AML cells that carry mutations known to cause venetoclax resistance.

"In this model, venetoclax alone did not extend survival at all - just as we would expect based on 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 that follows the data

Stewart says the project is personally meaningful.

“I am a breast cancer survivor and treated here at OHSU, so I know what it is 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 the opportunity to contribute."

Both researchers emphasized the importance of following scientific data, even if it goes beyond traditional boundaries.

“Some may wonder why a breast cancer drug would work for AML,” Tyner said. "But biology can be shared across very different types of cancer. This is a great example of why it's important to keep an open mind and follow the data where it leads."

Stewart said the team is already evaluating other drugs similar to palbociclib — many of which are also approved for breast cancer — to expand options for future clinical trials. Researchers hope to advance the combination toward clinical testing.

"We haven't tested it in patients yet, but based on everything we've seen, we expect this combination would attenuate most known mechanisms of resistance to current standard therapy," Tyner said. “It will take work to translate it into clinical reality, but that is exactly why we do what we do.”

Sources: