UC San Diego Researchers Overcome AML Drug Resistance with Novel Combination Therapy
核心洞察
UC San Diego researchers discovered why acute myeloid leukemia (AML) cells resist proteasome inhibitors by activating backup survival pathways regulated by HSF1 gene and autophagy systems.
The team successfully combined proteasome inhibitors with Lys05, an autophagy-impairing drug, to effectively kill AML cells and extend survival in preclinical models.
This mutation-agnostic approach worked across nearly all AML cell lines and patient samples tested, potentially expanding treatment options for the 70% of patients who die within five years.
University of California San Diego researchers have identified a promising new approach to treating acute myeloid leukemia (AML) by combining proteasome inhibitors with autophagy-blocking drugs, potentially overcoming a major barrier that has limited treatment options for patients with this aggressive blood cancer.
The study, published in Blood on October 20, 2025, reveals why AML cells have long resisted proteasome inhibitors—a class of drugs that work effectively in multiple myeloma. The research team discovered that AML cells activate backup stress-response systems to survive when their primary protein recycling machinery is blocked.
AML's Survival Strategy Revealed
AML, the most common adult leukemia, is notoriously difficult to treat, with approximately 70% of patients dying within five years of diagnosis. Current therapies are either broadly toxic, like chemotherapy, or narrowly focused on rare genetic mutations.
Robert Signer, Ph.D., senior author and associate professor in the Division of Regenerative Medicine at UC San Diego School of Medicine, explained the cellular mechanism using a traffic analogy: "Imagine you're driving down the highway and you hit construction, you just take an alternate route. When AML cells hit the 'construction' of proteasome inhibitors, they do the same thing by rewiring their network to take an off-ramp and continue their way. Multiple myeloma, on the other hand, remains stuck in traffic and becomes a sitting duck."
The research team demonstrated that unlike multiple myeloma cells, AML cells can activate backup systems regulated by the HSF1 gene or autophagy—a cellular waste management system—to maintain health when proteasomes are disabled. These emergency salvage and recycling pathways prevent protein "trash" from accumulating, allowing AML cells to resist death.
Combination Therapy Shows Promise
By combining proteasome inhibitors with Lys05, a drug that impairs autophagy, the researchers successfully shut down AML's survival 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."
Broad Therapeutic Potential
The approach demonstrated effectiveness across a variety of AML cell lines and patient samples, working across nearly all of them regardless of their mutations. This mutation-agnostic strategy could potentially benefit a much broader patient population compared to current targeted therapies.
The researchers leveraged their expertise on stem cells—from which AML cells form, unlike multiple myeloma cells—to develop this alternate treatment pathway. Signer noted that "targeting these protein pathways is a new approach to cancer treatment."
Next Steps Toward Clinical Translation
The research team is now working to identify additional drugs that could disable AML's backup survival strategies, with the goal of advancing combination therapies into clinical trials. The study represents a significant step forward in understanding AML's resistance mechanisms and developing more effective treatment strategies for this challenging cancer.
The research was supported by multiple National Institutes of Health grants, the American Society of Hematology, Blood Cancer United, the Mark Foundation for Cancer Research, and other organizations. The authors declared no competing interests.