A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-12, Vol.79 (23), p.5907-5914
• Main Authors: Xu, Shili, Herschman, Harvey R
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell Line, Tumor; Glycolysis - drug effects; Glycolysis - genetics; Hexokinase - antagonists & inhibitors; Hexokinase - genetics; Hexokinase - metabolism; Humans; Liver - drug effects; Liver - metabolism; Metformin - pharmacology; Metformin - therapeutic use; Mice; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Onium Compounds - pharmacology; Onium Compounds - therapeutic use; Oxidative Phosphorylation - drug effects; Perhexiline - pharmacology; Perhexiline - therapeutic use; RNA, Small Interfering - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-19-1789

Since Warburg's observation that most cancers exhibit elevated glycolysis, decades of research have attempted to reduce tumor glucose utilization as a therapeutic approach. Hexokinase (HK) activity is the first glycolytic enzymatic step; despite many attempts to inhibit HK activity, none has reached clinical application. Identification of HK isoforms, and recognition that most tissues express only HK1 while most tumors express HK1 and HK2, stimulated reducing HK2 activity as a therapeutic option. However, studies using HK2 shRNA and isogenic HK1 HK2 and HK1 HK2 tumor cell pairs demonstrated that tumors expressing only HK1, while exhibiting reduced glucose consumption, progressed as well as tumors expressing both HK1 and HK2. However, HK1 HK2 tumor subpopulations exist among many cancers. shRNA HK2 suppression in HK1 HK2 liver cancer cells reduced xenograft tumor progression, in contrast to HK1 HK2 cells. HK2 inhibition, and partial inhibition of both oxidative phosphorylation and fatty acid oxidation using HK2 shRNA and small-molecule drugs, prevented human liver HK1 HK2 cancer xenograft progression. Using human multiple myeloma xenografts and mouse allogeneic models to identify potential clinical translational agents, triple therapies that include antisense HK2 oligonucleotides, metformin, and perhexiline prevent progression. These results suggest an agnostic approach for HK1 HK2 cancers, regardless of tissue origin.