Reinforcing the need to look beyond genomic alterations to understand the complexity of cancer, researchers report that a normal enzyme called SYK pairs with FLT3, the most commonly mutated enzyme found in acute myelogenous leukemia (AML), to promote progression of the disease.
This molecular partnership also promotes the resistance of AML cells to treatment with FLT3-blocking drugs, potentially explaining the relatively poor showing of FLT3 inhibitors in multiple clinical studies. In an animal model of AML, treatment with a combination of FLT3- and SYK-inhibiting drugs was significantly more effective than treatment with either drug alone.
The findings were published in Cancer Cell (2014; doi:10.1016/j.ccr.2014.01.022) and come from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston, Massachusetts. The study raises hopes that treatment strategies that focus on both enzymes simultaneously could help bring molecularly targeted treatments to AML, a common blood cancer. The study also may have broader implications for how clinicians approach the development of such treatments and understand mechanisms behind resistance to treatment in other cancers.
Approximately 14,600 Americans are expected to receive a diagnosis of AML this year; children account for about 18% of patients. The overall outlook for AML patients is mixed; although the majority of patients with AML achieve remission with treatment, many relapse. The cancer cells of some 20% of adult patients and 15% of pediatric patients harbor a genomic alteration called FLT3-ITD, in which segments of the FLT3 enzyme are duplicated again and again, making the enzyme overactive.
“Patients whose AML cells express FLT3-ITD are among the highest risk group of patients with AML,” said the study’s senior author, Kimberly Stegmaier, MD, of Dana-Farber. “Their AML is particularly difficult to treat.”
FLT3 is a kinase, a molecular switch that routs signals for growth, division, and other processes within cells. Many cancers harbor mutations or other alterations that leave kinases stuck in the “on” position. This knowledge laid the foundation for the targeted cancer treatment revolution inaugurated by imatinib (Gleevec), which has made another blood cancer, chronic myelogenous leukemia, a controllable, chronic disease for many patients. However, patients with AML have not yet benefitted from that revolution.
Through experiments in cell lines, primary patient samples, and animal models, the research team found that the interaction of SYK and FLT3-ITD is a key ingredient in the progression of myeloproliferative disorder, a related blood cell disorder, into AML. The continued growth of AML cells after turning malignant also relied on these interactions.
In addition, the team found that SYK’s hyperactivated form can promote resistance to the FLT3-targeting drug quizartinib (AC220, Ambit Biosciences; San Diego, California). They could overcome this resistance with a combination of quizartinib and the SYK-blocking molecule PRT062607 (Portola Pharmaceuticals, South San Francisco, California), significantly increasing survival and reducing signs of disease in an FLT3-ITD AML mouse model.
Highlighting their findings’ clinical relevance, the researchers found strong SYK activity in cells from FLT3-ITD AML patients. The cells were also highly sensitive to SYK inhibition.