An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1(-)HK2(+) Multiple Myeloma

摘要

Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1(+)HK2(+) cancers, HK1(-)HK2(+) cancer subsets are sensitive to cytostasis induced by HK2(shRNA) knockdown and are also sensitive to synthetic lethality in response to the combination of HK2(shRNA) knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma cell lines are HK1(-)HK2(+). Here we describe an antisense oligo-nucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human multiple myeloma cell cultures and human multiple myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in multiple myeloma cells in culture and prevented HK1(-)HK2(+) multiple myelomatumor xenograft progression. DPIwas replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2(mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine multiple myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1(-)HK2(+) multiple myeloma.