Preclinical Evaluation of AMG 925, a FLT3/CDK4 Dual Kinase Inhibitor for Treating Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses. Mol Cancer Ther; 13(4); 880-9. Ó2014 AACR.

AMG 925 Is a Dual FLT3/CDK4 Inhibitor with the Potential to Overcome FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

“…All of these mutants were resistant to AC220 and sorafenib to various degrees. The data from Ba/ F3 cells expressing FLT3-ITD/D835Y are supportive of our earlier results that AMG 925 inhibited FLT3-ITD/D835Y/V human AML cells that are resistant to sorafenib and AC220 (18). Although Ba/ F3 cells expressing FLT3-ITD/F691I showed some resistance to AMG 925, it was worth noting that the resistance to AMG 925 was to a smaller degree compared with that of AC220 and sorafenib.…”

“…As previously reported (18,19), AMG 925 is a potent and selective dual FLT3/CDK4 inhibitor. It potently inhibits FLT3 and CDK4 kinases and the growth of FLT3-dependent AML cell lines bearing FLT3-ITD, MOLM13, and MV4-11 (Supplementary Table S1 Table S1).…”

“…AMG 925 is an FLT3/CDK4 dual inhibitor recently developed to overcome the resistance issue of selective FLT3 inhibitors by combining FLT3-and CDK4-inhibiting activities in one molecule (18,19). CDK4 has long been pursued as a genetically validated cancer drug target for a broad spectrum of Rb þ cancers, including AML (24,25,37).…”

“…Immunoprecipitation Western blotting for T-FLT3 and P-FLT3 was performed as previously described (18).…”

“…AMG 925 is a novel potent and selective FLT3/CDK4 dualkinase inhibitor designed to address the issue of resistance to FLT3 inhibitors (18,19). CDK4 is a Cyclin D-dependent kinase that plays an essential role in integrating external growth signals and promoting progression from G 1 to S phase of the mammalian cell cycle (20,21).…”