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

Abstract

Resistance to FLT3 inhibitors is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG 925, a dual FLT3/CDK4 inhibitor, has been developed to overcome this resistance. It is hypothesized that the combined inhibition of FLT3 and CDK4 may reduce occurrence of the FLT3 resistance mutations, and thereby prolong clinical responses. To test this hypothesis, we attempted to isolate AML cell clones resistant to AMG 925 or to FLT3 inhibitors. After a selection of over 8 months with AMG 925, we could only isolate partially resistant clones. No new mutations in FLT3 were found, but a 2-to 3-fold increase in total FLT3 protein was detected and believed to contribute to the partial resistance. In contrast, selection with the FLT3 inhibitors sorafenib or AC220 (Quizartinib), led to a resistance and the appearance of a number of mutations in FLT3 kinase domains, including the known hot spot sites D835 and F691. However, when AC220 was combined with the CDK4 inhibitor PD0332991 (palbociclib) at 0.1 mmol/L or higher, no resistance mutations were obtained, indicating that the CDK4-inhibiting activity of AMG 925 contributed to the failure to develop drug resistance. AMG 925 was shown to potently inhibit the FLT3 inhibitor-resistant mutation D835Y/ V. This feature of AMG 925 was also considered to contribute to the lack of resistance mutations to the compound. Together, our data suggest that AMG 925 has the potential to reduce resistance mutations in FLT3 and may prolong clinical responses.

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

“…A novel compound with dual activity against both CDK4/CDK6 and FLT3 has been recently reported [15, 16]. This inhibitor, AMG 925, inhibits AML cell growth in preclinical models and seems to prevent the emergence of resistant clones in FLT3-ITD positive AML cells, a major concern in AML therapy.…”

“…In addition, CDK4 was recently proposed as a therapeutic target in AML [15, 16]. However, the molecular mechanisms involved in the activation of the CDK/Cyclin D complex in AML are largely unknown at present time.…”

Improvement in clinical outcome of FLT3 ITD mutated acute myeloid leukemia patients over the last one and a half decade

“…Notably, sorafenib, quizartinib and other FLT3 inhibitors have shown minimal to no inhibitory activity against this mutation in preclinical models. New FLT3 inhibitors with in vitro activity against resistance mutations, such as crenolanib , ASP2215, and FLX925 (previously known AMG925) are currently being explored in the clinic .…”

FLT3 Inhibitors for Treating Acute Myeloid Leukemia

“…Several agents (AMG 925, SAR302503, Ponatinib, G-749..) might overcome FLT3 Inhibitor resistance as shown in some preclinical studies (55)(56)(57)(58).…”