A dual kinase inhibitor has shown early promise as a potential treatment for multiple myeloma (MM), according to investigators.
The inhibitor, ON123300, targets both AMPK-related protein kinase 5 (ARK5) and cyclin-dependent kinase 4 (CDK4), proteins responsible for maintaining energy balance within the cell.
Investigators found that ON123300 can induce apoptosis in MM cells in vitro and halt tumor growth in mouse models of MM.
The team reported these findings in Cancer Research.
“ARK5 is critical for myeloma survival, and this study suggests a novel function for ARK5 in bridging the mTOR and MYC pathways,” said study author Deepak Perumal, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“Given that MYC is critically overexpressed in myeloma, we sought to determine whether selective inhibition of ARK5 and CDK4 could be an effective way to target MYC-driven proliferation in myeloma.”
The team at Mount Sinai developed ON123300 in collaboration with Onconova Therapeutics, Inc. And they tested the drug in MM cell lines and primary samples from patients with recurring MM, as well as human HS-5 bone marrow stromal cells.
ON123300 induced rapid cell-cycle arrest and apoptosis in MM cells but was not toxic to normal peripheral blood cells.
In mouse models of MM, ON123300 decreased tumor growth without causing significant toxicity.
The investigators also discovered that MM cells that are sensitive to ON123300 have a unique genomic signature, which could guide the clinical development of the drug.
“Our study results show that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells,” said Samir Parekh, MD, also of the Icahn School of Medicine at Mount Sinai.
“This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in MM and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for MM patients.”
