Can Dasatinib Overcome Resistance to FLT3 Inhibition in AML?
Posted: Wednesday, September 16, 2020
A conditioned medium, which is produced by bone marrow support cells, allows FLT3-ITD+ acute myeloid leukemia (AML) cells to resist quizartinib-induced growth inhibition and continue to survive. However, Michael W. Deininger, MD, PhD, of the University of Utah, and colleagues propose that it may be possible to overcome this resistance by adding dasatinib to quizartinib, thereby shutting down alternate survival pathways. These findings were in the journal Leukemia.
“These data provide a rationale for the combined use of quizartinib and dasatinib in FLT3-ITD+ mutated AML and support further investigation into the mechanisms underlying the efficacy of this combination,” concluded the authors.
Researchers utilized blood and bone marrow samples from patients with AML as well as several FLT3-ITD+ AML cell lines to conduct viability assays, cell-proliferation assays, metabolic phenotyping, and immunoblot analysis. They cultured the FLT3-ITD+ AML cells along with the medium that was conditioned with human bone marrow stromal cells (conditioned medium) to mimic in vivo conditions. When grown within this conditioned medium, FLT3-ITD+ AML cells were protected from quizartinib, which normally inhibits FLT3. The evasion of quizartinib-mediated apoptosis was mostly through activation of the STAT5 pathway. Additionally, extrinsic STAT5 was found to be a driver for the survival of leukemic cells as an alternative pathway when FLT3 was inhibited.
The team then decided to inhibit the STAT5 pathway by adding a variety of different known to inhibit proximal kinases involved in STAT5 activation: ruxolitinib (Janus kinase 2), ibrutinib (Bruton’s tyrosine kinase), and dasatinib (Src family kinases). The combination of dasatinib and quizartinib appeared to be the most effective at decreasing by 50% the maximal inhibitor concentration of quizartinib in AML cells grown with media made by bone marrow stromal cells. There was also a notable decrease in glycolytic activity of AML cells grown in conditioned media when they were treated with dasatinib and quizartinib.
Disclosure: For disclosures of the study authors, visit nature.com.