An innovative combination of treatment strategies involving myeloid cell leukemia (MCL)-1 inhibitors and a kinase inhibitor targeting the SRC oncogene could be effective at triggering cell death in acute myeloid leukemia (AML) cells, according to a recent study published by Hu et al in Signal Transduction and Targeted Therapy.
Background
AML is often an incurable type of cancer, with a median survival of less than 9 months and a 5-year survival rate of just over 30%, according to data from the National Cancer Institute. The disease develops from the uncontrolled growth and survival of undifferentiated leukemia stem cells. These stem cells are particularly dependent on the MCL-1 protein, which plays an important role in regulating leukemia cell death.
Although many drugs have been developed to treat the disease over the past several years, AML remains highly resistant to standard therapies or recurs after treatment—with the exception of a subset of patients who are eligible for bone marrow transplantation.
However, MCL-1 inhibitors have become an area of considerable interest in the treatment of leukemia as well as other hematologic malignancies. Preclinical studies have demonstrated that these agents effectively block the function of MCL-1, reducing the ability of AML cells to survive. Nonetheless, MCL-1 inhibitors and other drugs of the class collectively referred to as BH3 mimetics simultaneously trigger the accumulation of MCL-1 within leukemia cells. This buildup antagonizes the antileukemic activity of MCL-1 inhibitors, and strategies to oppose this outcome have not yet been identified.
“Cancer cells are known for their ability to develop alternative protective pathways that allow them to survive exposure to agents that interrupt signaling cascades,” detailed co–senior study author Steven Grant, MD, Professor of Internal Medicine at the Virginia Commonwealth University (VCU) School of Medicine and Associate Director for Translational Research at the Massey Comprehensive Cancer Center at VCU. “If [we] can identify those escape pathways and disable them, there is a much better chance of killing the cells,” he added.
Study Methods and Results
In this study, researchers sought to develop a strategy to prevent the accumulation of MCL-1 in AML cells. They found that the addition of the SRC inhibitor was effective at overcoming MCL-1 accumulation in the cells exposed to MCL-1 inhibitors.
They hypothesized that the phenomenon stemmed from three separate but intertwined processes. Of note, the MCL-1 inhibitor and SRC inhibitor regimen effectively killed primary AML cells but spared their normal counterparts. The regimen was well tolerated in mouse models and significantly improved survival in patient-derived xenograft models.
Comprehensive analysis also revealed additional disturbances in cellular signaling pathways that might also contribute to the antileukemic activity of the SRC/MCL-1 inhibitor combination strategy.
Conclusions
“Results from this research could add another approach to the therapeutic armamentarium against leukemia,” suggested Dr. Grant.
The findings revealed that SRC inhibitors may improve the activity of MCL-1 inhibitors against AML in the clinical setting. Currently, administration of MCL-1 inhibitors is limited by the potential of these drugs to induce cardiovascular complications, but multiple pharmaceutical companies are developing newer versions of these drugs that are minimally associated with this cardiac toxicity.
The researchers hope to determine whether SRC inhibitors can enhance the antileukemic activity of the novel MCL-1 inhibitors with a limited and safe level of toxicity. If successful, future studies could serve as a foundation for the development of clinical trials employing the SRC/MCL-1 inhibitor strategy in patients with relapsed or refractory AML.
“This is an important discovery in AML, but it’s a reflection of an approach that Dr. Grant has been a pioneer in for many years,” underscored co–senior study author Gordon D. Ginder, MD, a member of the Cancer Biology research program at the Massey Comprehensive Cancer Center at VCU. “These findings support a clinical approach to make targeted therapy actually work in the majority of deadly cancers, which often have escape mechanisms for survival when their primary driver is targeted. That’s the bottom line,” he concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.
