Melanoma Drug May Help Overcome Resistance to Leukemia Treatments
For Immediate Release
October 12, 2017
Adding trametinib, a melanoma drug that inhibits a protein called MEK, to currently used therapies for a common form of acute myelogenous leukemia (AML) may strengthen response to the therapies and potentially improve survival, Johns Hopkins Kimmel Cancer Center pediatric oncology researchers have demonstrated in studies of human cells and mice. The work was published online Sept. 18 in the journal Cancer Research.
The research was conducted in models of AML with mutations of the FLT3 gene. FLT3 is one of the most commonly mutated genes in AML. The most frequently observed genetic alteration, the internal tandem duplication (ITD), occurs in about 23 percent of patients with AML and is associated with a poor prognosis, says study co-author Christine A. Pratilas, M.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine and interim director of the Kimmel Cancer Center’s Sarcoma Program.
Several FLT3 inhibitor drugs are currently used in the management of FLT3-mutated AML, Pratilas says, but they don’t result in durable responses, and some patients don’t respond at all. “There is an unmet need for better therapies for patients with FLT3-mutated AML, and we need to improve upon currently available targeted therapies for that condition. One way to do that would be to develop a better inhibitor or to test combination therapy,” she says.
In some cancers driven by mutated genes, Pratilas says, inhibiting one target, like FLT3, can result in reactivation of other signaling pathways, a process she calls adaptive resistance. This could explain why the cancers don’t respond to the treatments.
“Signaling pathways are not simple — we don’t just inhibit A and that turns off B, C and D, and that’s the end of the story,” she says. “When we inhibit A, we do inhibit B, C and D, but D might be doing something else to another pathway and also exerting what we call negative feedback, limiting signaling throughout the pathway.”
To better understand signaling adaptation in these cancers, Pratilas and colleagues studied the application of various FLT3 inhibitors in both FLT3-mutated AML human cells and in a mouse model of FLT3-mutated AML. In a series of experiments, they observed a rebound in ERK activation within 16 to 24 hours after treatment with FLT3 inhibitors in human and mouse cells. ERK is part of a cell signaling pathway that is active during cancer formation and progression, and helps transmit signals from receptors on the surface of cells to DNA within the cell. Even retreating the cells didn’t help; ERK remained active and increased to pretreatment levels within 48 hours.
Additional experiments demonstrated that adding MEK inhibitors like trametinib, even at low concentrations, significantly reduced the degree of ERK rebound in human AML cell lines and the mouse model, and helped sensitize AML cells to the FLT3 inhibitors, resulting in increased cancer cell death. The combination treatment also significantly reduced leukemia cells seen in the blood and bone marrow of mice. Researchers additionally observed a similar rebound in ERK signaling following treatment in models of BCR-ABL leukemia — a type of leukemia characterized by the fusion of two genes — EGFR-driven lung cancer and HER2-amplified breast cancer that also could be overcome by adding a MEK inhibitor.
Interestingly, Pratilas says, trametinib, which is FDA-approved for the treatment of melanoma, on its own does not yield a response against AML.
Scientists who contributed to the work include J. Kyle Bruner, Hayley S. Ma, Li Li, Alice Can Ran Qin, Michelle A. Rudek, Richard J. Jones, Mark J. Levis, Keith W. Pratz and Donald Small. The work was supported by a National Institutes of Health research grant (R01CA090668), an NIH project grant (P30CA006973) and the Giant Food Pediatric Cancer Research Fund. Small also is supported by the Kyle Haydock Professorship.