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New therapeutic target: CDK4/ARK5 inhibition in multiple myeloma


Despite new therapies, multiple myeloma remains incurable causing most patients to ultimately develop drug resistance and succumb to the disease. The pursuit of drugs that inhibit cell cycle regulators especially cyclin-dependent kinases ( CDKs ), has been an intense focus of research in cancer.

A new study by researchers at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai has shown that targeting both CDK4 and ARK5, proteins responsible for maintaining energy balance within the cell, was extremely effective in causing cell death in myeloma.
Their research, published in the journal Cancer Research, identifies new targets for myeloma drug development.

Multiple myeloma is a fatal blood cancer accounting for over 10,000 deaths in the United States each year. Better understanding of the molecular basis of myeloma has led to a growing list of treatments for this challenging disease. Despite recent advances in new therapies, this disease remains incurable with a median survival of 7 to 8 years.

Researchers at Icahn School of Medicine along with Onconova Therapeutics, developed a compound, ON123300 that included multi-targeted inhibitors ARK5 and CDK4.
The researchers treated both primary myeloma cells and cells line with ARK5/CDK4 inhibitor ON123300 which resulted in tumor cell death, and halted cancer cell growth in vitro and in vivo mouse models.

ARK5 is critical for myeloma survival and this study suggests a novel function for ARK5 in bridging the mTOR and MYC pathways.
Given that MYC is critically over expressed in myeloma, researchers sought to determine whether selective inhibition of ARK5 and CDK4 could be an effective way to target MYC-driven proliferation in myeloma.

Researchers evaluated the effect of ARK5/CDK4 inhibitor ON123300 against myeloma cell lines and primary samples from patients with recurring myeloma.
Myeloma cells were sensitive to ON123300 while normal peripheral blood cells were spared from the effects of the compound confirming a potent and specific anti-cancer effect of ON123300.

The study has shown that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells.
This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in multiple myeloma and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for these patients. ( Xagena )

Source: Mount Sinai Health System, 2016

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