Data from An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1<sup>−</sup>HK2<sup>+</sup> Multiple Myeloma

Abstract

<div>Abstract<p>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<sup>+</sup>HK2<sup>+</sup> cancers, HK1<sup>−</sup>HK2<sup>+</sup> cancer subsets are sensitive to cytostasis induced by HK2<sup>shRNA</sup> knockdown and are also sensitive to synthetic lethality in response to the combination of HK2<sup>shRNA</sup> 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<sup>−</sup>HK2<sup>+</sup>. Here we describe an antisense oligonucleotide (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<sup>−</sup>HK2<sup>+</sup> multiple myeloma tumor xenograft progression. DPI was 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<sup>−</sup>HK2<sup>+</sup> multiple myeloma.</p>Significance:<p>A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in <i>in vivo</i>, presenting an effective, tolerated combination therapy for preventing progression of HK1<sup>−</sup>HK2<sup>+</sup> multiple myeloma tumors.</p></div>