Acute myeloid leukemia (AML) has long stood as one of the most daunting adversaries in the world of oncology. Despite decades of research and the advent of numerous cancer therapies, AML continues to claim the lives of approximately 70% of those diagnosed within five years—a statistic that has barely budged, even as related blood cancers have seen significant improvements in outcomes. What makes AML so stubbornly lethal? A new study from the University of California San Diego, published in Blood on October 20, 2025, is shedding light on this very question—and, perhaps more importantly, pointing the way toward more effective treatments.
Unlike its cousin, multiple myeloma, which responds well to a class of drugs known as proteasome inhibitors, AML has proven remarkably resistant. Proteasomes are the cell’s equivalent of garbage disposals, tasked with breaking down and recycling damaged or unnecessary proteins. In multiple myeloma, blocking these proteasomes leads to a toxic buildup of protein waste, triggering stress and ultimately cell death. But in AML, the story is different. According to UC San Diego’s research team, led by Dr. Robert Signer, AML cells possess a crafty ability to sidestep this blockade by activating alternative routes for protein disposal.
“Imagine you’re driving down the highway and you hit construction, you just take an alternate route,” Dr. Signer explained in a statement to UC San Diego Today. “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.”
These “off-ramps” are twofold: one is regulated by the heat shock factor 1 (HSF1) gene, and the other is autophagy—a self-digestive process that allows cells to recycle damaged organelles and proteins. By shunting protein waste through these backup pathways, AML cells avoid the fate that befalls multiple myeloma cells under similar treatment. This biological detour not only explains why proteasome inhibitors fall short in AML, but also points to a potential solution: block both the main route and the detours, and you just might trap AML cells with nowhere to go.
That’s precisely the approach the UC San Diego team took. In their experiments, they combined proteasome inhibitors with Lys05, a drug that disrupts autophagy by interfering with the lysosomal degradation pathway. The results were striking. In cultured AML patient cells, the combination therapy significantly reduced cancer cell viability and colony formation. Mice treated with this dual regimen not only showed a marked reduction in disease burden but also lived longer—without suffering major side effects. These findings, as reported in Blood, could open the door to broader, more effective treatment options for patients who have few good choices today.
One of the most promising aspects of this strategy is its so-called “mutation-agnostic” nature. Dr. Kentson Lam, first author on the study and assistant clinical professor of medicine at UC San Diego, explained the advantage: “Because AML involves so many potential gene mutations, it has made developing therapies quite difficult. 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.”
In other words, while previous therapies have often zeroed in on particular genetic mutations—benefiting only those patients whose leukemia fit the genetic profile—this new combination therapy appears to work across the board. That’s a big deal in a disease as genetically diverse as AML, where no one mutation is responsible for the majority of cases.
The study’s significance goes beyond just the mechanics of protein disposal. It represents a shift in how scientists think about treating AML. Instead of focusing solely on genetic mutations, the research highlights the vulnerability of cancer cell metabolism and protein homeostasis—essentially, the cell’s ability to keep its internal environment in balance. By targeting the stress-response and degradation systems that AML cells rely on for survival, researchers hope to tip the scales in favor of cell death, even in the face of the cancer’s notorious adaptability.
This approach is informed, in part, by the team’s deep expertise in stem cell biology. Unlike multiple myeloma, which arises from plasma cells, AML originates from hematopoietic stem cells. These cells possess unique physiological traits that make them especially resilient. By understanding the molecular circuitry that governs stem cell proteostasis, the UC San Diego team was able to devise a strategy that targets multiple recycling pathways at once—cutting off the cancer’s escape routes and overwhelming its defenses.
Of course, these findings are still in the preclinical stage. The next step, as Dr. Signer and his colleagues emphasize, is to identify additional compounds that can further disable AML’s backup survival strategies—especially those regulated by the HSF1 gene. The ultimate goal is to move these combination therapies into clinical trials, where they can be tested in patients and, if successful, become part of the standard arsenal against AML.
“Our hope is that this new research will improve treatment options for a wide range of AML patients,” Signer said. “As scientists, that is our ultimate goal: to find new ways to treat disease to improve lives.”
The research was supported by a wide range of funding sources, including the National Institutes of Health, the American Society of Hematology, the Mark Foundation for Cancer Research, and several other organizations dedicated to advancing cancer research. The collaborative effort drew on expertise from multiple departments at UC San Diego, as well as international partners.
For patients and families grappling with AML, these findings offer a glimmer of hope. While the fight against AML is far from over, the discovery of how the disease sidesteps current treatments—and how those evasive maneuvers can be blocked—represents a critical step forward. It’s a reminder that even the most complex cancers can yield their secrets to determined investigation, and that new strategies can emerge from a deeper understanding of the basic biology that underpins disease.
As the medical community awaits the results of future clinical trials, the promise of more effective, less toxic, and more widely applicable therapies for AML feels closer than ever before. For now, the message is clear: the roadblocks that once protected AML may finally be coming down, thanks to a new understanding of the detours cancer cells take—and how to close them off for good.
