Dual Drug Approach Targets Acute Myeloid Leukemia

Acute myeloid leukemia (AML), an aggressive and often fatal blood cancer, has long resisted a class of drugs called proteasome inhibitors, which work well in multiple myeloma. A new study by University of California San Diego researchers shows why: AML cells activate backup stress-response systems to stay alive when proteasomes are blocked. Proteasomes are cellular machines responsible for breaking down and recycling proteins, allowing cells to stay healthy. By combining proteasome inhibitors with a second drug that disables one of two backup survival pathways, the team was able to kill AML cells more effectively, reduce disease burden and extend survival in preclinical models. The findings, published in Blood on Oct. 20, 2025, could open the door to broader treatment options for patients.

The most common adult leukemia, AML is notoriously difficult to treat. About 70% of patients die within five years of diagnosis. Current therapies are either broadly toxic, like chemotherapy, or narrowly focused on rare genetic mutations.

By combining proteasome inhibitors with Lys05, a drug that impairs autophagy, the team was able to shut down AML’s detour. In tests on AML patient cells, the combination slowed cancer cell growth and colonization. Treated mice lived longer without major side effects.

“Because AML involves so many potential gene mutations, it has made developing therapies quite difficult,” said Kentson Lam, M.D., Ph.D., first author and assistant clinical professor of medicine at UC San Diego School of Medicine. “When therapies targeting specific gene mutations are successful, they only benefit the small subset of patients whose cancer carries those specific mutations. We wanted to help more patients by making this attack more mutation-agnostic. We tested this approach across a variety of AML cell lines and patient samples, and it worked across nearly all of them, regardless of their mutations.”

The researchers are now working to identify additional drugs that could disable AML’s backup survival strategies, with the goal of advancing combination therapies into clinical trials.

“Targeting these protein pathways is a new approach to cancer treatment,” Signer said, adding that he and his team leveraged their expertise on stem cells — from which AML cells form, unlike multiple myeloma cells — to forge an alternate pathway for treatment.

“Our hope is that this new research will improve treatment options for a wide range of AML patients,” Signer noted. “As scientists, that is our ultimate goal: to find new ways to treat disease to improve lives.”