Normal Enzyme Pairs With Mutated FLT3 to Fuel AML Progression
Findings from a study by Puissant et al suggest that the wild-type form of enzyme SYK pairs with FLT3, the most commonly mutated enzyme found in acute myeloid leukemia (AML), to promote progression of the cancer. The molecular partnership also promotes AML cells’ resistance to treatment with FLT3 inhibitors, possibly explaining the disappointing results of these agents in clinical trials. The study is published in Cancer Cell.
To better understand SYK’s role in the development of AML, researchers from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center screened AML cell lines to reveal the full scope of the enzyme’s molecular interactions. They found evidence of strong interactions between wild-type SYK and mutated FLT3—in particular, FLT3-ITD.
Study Method and Findings
Through experiments in cell lines, primary patient samples, and animal models, the scientists found that interactions between SYK and FLT3-ITD are key factors in the progression of myeloproliferative neoplasms into AML. AML cells’ continued growth after turning malignant also relied on these interactions.
In addition, the researchers found that SYK’s hyperactivated form can promote resistance to the FLT3-targeting drug quizartinib (AC220). However, the resistance could be overcome using a combination of quizartinib and the SYK inhibitor PRT062607, which significantly increased survival and reduced signs of disease in an FLT3-ITD AML mouse model.
Highlighting their findings’ clinical relevance, the researchers found strong SYK activity—and high sensitivity to SYK inhibition—in cells from FLT3-ITD AML patients.
Critical Target in AML
“These data affirm that SYK is an important target in AML,” Kimberly Stegmaier, MD, of Dana-Farber/Boston Children’s Hematologic Malignancies Center and a senior author of the study, said in a statement. “They also suggest that interactions between oncologic kinases and SYK or other wild-type enzymes may contribute to resistance of kinase inhibitors more broadly.”
Dr. Stegmaier also noted that over the course of this research, the researchers have developed a suite of tools that may aid in future clinical studies of treatments with SYK inhibitors or SYK inhibitors in combination with FLT3 inhibitors. These include biomarkers to identify patients with high levels of SYK and FLT3 activation. Patients with FLT3 mutations are more likely to respond to SYK inhibitors, and researchers can monitor these targets while patients undergo treatment.
According to the American Cancer Society, about 18,860 new cases of AML—mostly in adults—will be diagnosed this year in the United States.
Dr. Stegmaier is the corresponding author of the Cancer Cell article.
The study was supported by the National Cancer Institute, the American Cancer Society, the Starr Cancer Consortium, Project Cupid and One Mission, the Swedish Research Council, the Swedish Cancer Society, and the Leukemia and Lymphoma Society.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
