Combination therapy could expand treatment options for AML patients, extend survival

(Press-News.org) 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. 

New research by Robert Signer, Ph.D., senior author and an associate professor in the Division of Regenerative Medicine at UC San Diego School of Medicine, and team demonstrated why proteasome inhibitors alone are not effective against AML. Unlike multiple myeloma cells, AML cells can use a backup system regulated by the HSF1 gene, or autophagy — a different kind of waste management system — to maintain health when such drugs are used. These emergency salvage and recycling pathways keep protein “trash” from piling up, even when proteasomes are disabled, allowing AML cells to maintain health and resist death.

“Imagine you’re driving down the highway and you hit construction, you just take an alternate route,” said Signer, who is also deputy director of Sanford Stem Cell Institute’s Discovery Center and a member of UC San Diego Moores Cancer Center. “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.”

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.”

# # #

Additional co-authors on the study include Kentson Lam, Yoon Joon Kim, Eveyln L. Tan, Carlo M. Ong, Andrea Z. Liu, Fanny J. Zhou, Mary Jean Sunshine, Bernadette A. Chua, Silvia Vincenzi, Katelyn Chen and Leslie A. Crews, of the University of California San Diego Sanford Stem Cell Institute’s Stem Cell Discovery Center; Pierce W. Ford and Eric J. Bennett, of the University of California San Diego School of Biological Sciences’ Department of Cell and Developmental Biology; Jie-Hua Zhou and Edward D. Ball, of the University of California San Diego School of Medicine’s Division of Blood and Marrow Transplant, and the Moores Cancer Center; Yuning Hong of La Trobe University’s La Trobe Institute for Molecular Science’s Department of Biochemistry and Chemistry, in Melbourne, Australia. They also include Helena Yu of the University of California San Diego Sanford Stem Cell Institute’s Stem Cell Discovery Center; Rady Children’s Hospital in San Diego, California; and the University of California San Diego Department of Pediatrics’ Division of Pediatric Hematology/Oncology.

The study was funded, in part, by the National Institutes of Health (NIH) (S10OD032316); NIH National Cancer Institute (T32CA121938, 2T32CA067754, U01CA267031, P30CA023100, R37CA252040); NIH National Center for Advancing Translational Sciences (KL2TR001444); NIH National Heart, Lung and Blood Institute (F31HL170531); NIH National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116951; R01DK124775); NIH National Institute on Aging (R01AG088725); an American Society of Hematology Scholar award; the Blood Cancer Discoveries Grant program (8025-20) through Blood Cancer United; the Mark Foundation for Cancer Research and the Paul G. Allen Frontiers Group; the Cancer Stem Cell Consortium supported by the American Cancer Society and the Lisa Dean Moseley Foundation (CSCCRSG-23-994830-01-CSCC) and a private family foundation; a Curebound Target grant; the UC San Diego Sanford Stem Cell Institute and its Sanford Stem Cell Discovery Center; the UC San Diego Moores Cancer Center; a California Institute of Regenerative Medicine fellowship (EDUC4-12804).

The authors declare no competing interests.

# # #

END