Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 5; pp. 1225 - 1236
• Main Authors: Perumal, Deepak, Kuo, Pei-Yu, Leshchenko, Violetta V, Jiang, Zewei, Divakar, Sai Krishna Athaluri, Cho, Hearn Jay, Chari, Ajai, Brody, Joshua, Reddy, M V Ramana, Zhang, Weijia, Reddy, E Premkumar, Jagannath, Sundar, Parekh, Samir
• Format: Journal Article
• Language: English
• Published: United States 01.03.2016
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - physiology; Gene Expression Profiling; Humans; Mice; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinases - physiology; Pyridones - pharmacology; Pyrimidines - pharmacology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - physiology; Sirtuin 1 - physiology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2934

Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma.