RT Journal Article
SR Electronic
T1 Hexokinase 2 Is Targetable for HK1-Negative, HK2-Positive Tumors from a Wide Variety of Tissues of Origin
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 212
OP 217
DO 10.2967/jnumed.118.212365
VO 60
IS 2
A1 Shili Xu
A1 Arthur Catapang
A1 Hanna M. Doh
A1 Nicholas A. Bayley
A1 Jason T. Lee
A1 Daniel Braas
A1 Thomas G. Graeber
A1 Harvey R. Herschman
YR 2019
UL http://jnm.snmjournals.org/content/60/2/212.abstract
AB Although absent in most adult tissues, hexokinase 2 (HK2) is expressed in most tumors and contributes to increased glucose consumption and to in vivo tumor 18F-FDG PET signaling. Methods: Both HK2 knockdown and knockout approaches were used to investigate the role of HK2 in cancer cell proliferation, in vivo xenograft tumor progression, and 18F-FDG tumor accumulation. BioProfiler Glycolysis analysis monitored cell culture glucose consumption and lactate production; 18F-FDG PET/CT monitored in vivo tumor glucose accumulation. Cancer Cell Line Encyclopedia data were analyzed for hexokinase 1 (HK1) and HK2 expression. Results: Neither cell proliferation in culture nor xenograft tumor progression are inhibited by HK2 knockdown or knockout in cancer cells that express HK1 and HK2. However, cancer subsets from a variety of tissues of origin express only HK2, but not HK1. In contrast to HK1-positive/HK2-positive (HK1+HK2+) cancers, HK2 knockdown in HK1-negative (HK1−) HK2+ cancer cells results in inhibition of cell proliferation, colony formation, and xenograft tumor progression. Moreover, HK1-knockout (HK1KO)HK2+ cancer cells are susceptible to HK2 inhibition, in contrast to their isogenic HK1+HK2+ parental cells. Conclusion: HK1 and HK2 expression are redundant in tumors; either can provide sufficient aerobic glycolysis for tumor growth, despite a reduction in 18F-FDG PET signal. Therapeutic HK2 inhibition is likely to be restricted to HK1−HK2+ tumor subsets, and stratification of tumors that express HK2, but not HK1, should identify tumors treatable with emerging HK2 specific inhibitors.