Targeting FLT3 and Src Pathways: The Role of ON150030 in Advanced AML Treatment

Acute Myeloid Leukemia (AML) is often linked with the FLT3 Internal tandem duplication mutation (FLT3-ITD), which is found in about a third of cases. This mutation leads to increased cell proliferation and inhibition of apoptosis. Quizartinib, a second-generation FLT3 inhibitor, has shown efficacy in treating AML but has a limited response duration due to secondary mutations like D835X, which render FLT3 constitutively active. Type 2 inhibitors, such as Quizartinib, are ineffective against this mutated form of FLT3.

A novel therapeutic agent, ON150030, has been developed to overcome this challenge. Structural studies indicate that ON150030 binds to the active form of FLT3, making it a Type 1 inhibitor. This allows ON150030 to inhibit both wildtype and mutant forms of FLT3, including those with the D835Y mutation, which Quizartinib cannot. ON150030 has demonstrated potent inhibitory effects on FLT3 in vitro and is characterized as an irreversible inhibitor.

Biological studies have shown that ON150030 specifically inhibits the growth of MV4-11 cells with the FLT3-ITD mutation and reduces the activity of MAPK and PI3K/AKT pathways. Additionally, it counteracts the JAK-independent phosphorylation of STAT5 associated with FLT3-ITD.

Future plans include examining the effects of FLT3 and its mutant isoforms on mouse myeloid cells and comparing the impacts of ON150030 and Quizartinib on these cells. Given that ON150030 also inhibits SRC, a known inducer of resistance to targeted therapies in leukemias, researchers will test the drug's sensitivity in cells with introduced SRC.

Cytotoxicity and biochemical assays are planned for patient-derived primary AML cells treated with ON150030. Mouse xenograft models will help determine the potential synergy of ON150030 with standard chemotherapy agents and its ability to inhibit cancer progression in vivo.

The ultimate goal of the project is to establish ON150030 as a viable component of combination therapies for all AML patients with FLT3 mutations, potentially leading to sustained remission.

The research was presented by Helya Ghaffari, M.V. Ramana Reddy, and colleagues at the American Association for Cancer Research Annual Meeting in 2017.