Acute Myeloid Leukemia Coverage From Every Angle

Third-Generation BCR-ABL Inhibitor Under Study in AML

By: Joseph Fanelli
Posted: Tuesday, July 28, 2020

The third-generation BCR-ABL inhibitor GZD824 appears to have the potential to suppress the signaling pathways of FLT3, FGFR1, and PDGFRα genes in patients with resistant acute myeloid leukemia (AML), according to preclinical research findings presented in Translational Oncology. The multikinase inhibitor may prove to be effective beyond BCR-ABL–driven chronic myeloid leukemia, concluded Ke Ding, PhD, of Jinan University, Guangzhou, China, and colleagues.

“[GZD824] overcomes FLT3-D835N/H/R/G/A, F691I, and G697R-mutant resistance and obviously suppresses the growth of F691I-mutant xenograft tumors in animals,” the researchers observed.

The authors isolated primary AML cells from patients. All the samples were enriched in leukemic cells by performing density-gradient separation to yield a mononuclear fraction, and part of the primary cells were extracted RNA.

At concentrations below 10 nM, GZD824 significantly suppressed FLT3, FGFR1, and PDGFRα kinase activities and inhibited the signaling pathways in several leukemia cells (MV4-11, KG-1, and EOL-1). In addition, GZD824 selectively prevented the growth of these cells and suppressed the growth of Ba/F3-FLT3-ITD cells that harbor F691I and other mutations with IC50 values less than 10 nM.

The multikinase inhibitor also induced G0/G1 phase arrest and apoptosis in MV4-11, KG-1, and EOL-1 cells and activated cleavage of caspase-3 and PARP. Based on xenograft mouse models of MV4-11, Ba/F3-ITD-F691I, and KG-1, GZD824 “almost completely” eliminated tumors at 10 or 20 mg/kg given every other day. In addition, GZD823 hindered the viability of primary leukemic blasts in patients with AML who had FLT3-ITD–positive disease, but not in patients with native FLT3-positive disease.

Disclosure: The authors reported no conflicts of interest.

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