New Combination Therapy Circumvents AML's Resistance to Proteasome Inhibitors

A new potent combination therapy may be capable of circumventing acute myeloid leukemia (AML) cells’ intrinsic resistance to proteasome inhibitors, a class of drugs that has worked well in multiple myeloma but have proven ineffective against AML.1 Findings published in Blood suggest that pairing a proteasome inhibitor with the autophagy inhibitor Lys05 synergistically kills AML cells, significantly reduces disease burden, and extends survival in preclinical models.

AML is the most common adult leukemia and is challenging to treat, with approximately 70% of patients dying within 5 years of their diagnosis.2,3 The current therapeutic strategies are often either broadly toxic, such as standard chemotherapy, or narrowly focused on rare genetic mutations, benefiting only a small subset of patients. Proteasome inhibitors, which are highly effective in treating multiple myeloma, have largely failed as monotherapies in AML.

Research by investigators at the University of California San Diego (UC San Diego) determined that AML cells possess robust, built-in backup systems that prevent the proteasome inhibitors from disrupting protein homeostasis (proteostasis), the process cells use to maintain health by managing protein breakdown and recycling. When proteasome inhibitors block the proteasomes, AML cells activate compensating stress-response pathways to keep protein "trash" from accumulating, thus staying healthy.

Robert Signer, PhD | Image Credit: © UC San Diego School of Medicine

“Imagine you’re driving down the highway and you hit construction; you just take an alternate route,” Robert Signer, PhD, senior author and an associate professor at UC San Diego School of Medicine, said in a statement.2 “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.”

How Targeting AML's Backup Systems Enhances Treatment Efficacy

By combining proteasome inhibitors, such as bortezomib or carfilzomib, with a second drug that disables the backup pathway, Signer and his colleagues were able to disrupt proteostasis and sensitize AML to proteasome inhibition. The combined inhibition of the proteasome and autophagy activated a terminal integrated stress response that induced programmed cell death in the leukemic cells.

In preclinical in vivo models, combined bortezomib and Lys05 treatment reduced the AML burden and significantly extended survival for xenograft recipients without causing major adverse effects. Furthermore, primary AML cells, including leukemic stem/progenitor cells, were significantly more sensitive to the combined treatment than normal hematopoietic stem/progenitor cells derived from healthy human donors, suggesting potential for low hematopoietic toxicity.

“Because AML involves so many potential gene mutations, it has made developing therapies quite difficult,” Kentson Lam, MD, PhD, first author and assistant clinical professor of medicine at UC San Diego School of Medicine, said in a statement.2 “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.”

References

1. Lam K, Kim YJ, Tan EL, et al. The proteostasis network is a therapeutic target in acute myeloid leukemia. Blood. Published online October 20, 2025. doi:10.1182/blood.2024026749

2. Prater E. Combination therapy could expand treatment options for AML patients, extend survival. News release. UCSD. October 20, 2025. Accessed October 22, 2025. https://today.ucsd.edu/story/combination-therapy-could-expand-treatment-options-for-aml-patients-extend-survival

3. Acute myeloid leukemia. The University of Texas MD Anderson Cancer Center. Accessed October 22, 2025. https://www.mdanderson.org/cancer-types/acute-myeloid-leukemia.html