Geldanamycin inhibits Jumonji histone lysine demethylase KDM4 and targets chimeric transcription factor PAX3-FOXO1
Year: 2019
Type: preprint
Abstract: Histone lysine demethylases (KDMs) are emerging as therapeutic targets in cancer. Development of potent KDM inhibitors may provide additional options for epigenomics-oriented therapies. Using a Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) functional demethylation assay, in combination with a high-content immunofluorescence imaging phenotypic screen, Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance mass spectrometry (MALDI-FTICR MS) and Amplified Luminescent Proximity Homogeneous Assay (ALPHA), we identified geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), as a novel inhibitor of JmjC-domain containing demethylases such as KDM4B. We further found that geldanamycin can destabilize the PAX3-FOXO1 fusion oncoprotein, an Hsp90 client, which is a driver of clinically unfavorable alveolar rhabdomyosarcoma (aRMS). We then hypothesized that dual inhibition of PAX3-FOXO1 and epigenetic modifiers of aRMS would have synergistic antitumor activity. We repurposed the geldanamycin analog 17-DMAG to target aRMS and found that 17-DMAG significantly delays tumor growth, extends survival in xenograft mouse models, and inhibits expression of PAX3-FOXO1 targets and multiple oncogenic pathways including MYC, E2F and NOTCH. In addition, the combination of 17-DMAG with conventional chemotherapy or the bromodomain inhibitor JQ1 significantly enhances therapeutic efficacy. In summary, we have identified geldanamycin and 17-DMAG as dual KDM/Hsp90 inhibitors and 17-DMAG is efficacious against PAX3-FOXO1-driven rhabdomyosarcoma.
Authors: Ahmed Abu-Zaid, Shivendra Singh, Wenwei Lin, Jonathan Low, Alireza Abdolvahabi, Bailey Cooke, John Bowling, Sivaraja Vaithiyalingam, Jie Fang, Duane Currier, Mi-Kyung Yun, Alaa AlTahan, Dinesh M. Fernando, Julie Maier, Heather Tillman, Purva Bulsara, Zhaohua Lu, Sourav Das, Zhenmei Li, Brandon Young, Richard Lee, Zoran Rankovic, Stephen White, Andrew M. Davidoff, Taosheng Chen, Jun Yang
Institution: St. Jude Children's Research Hospital
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Cancer Institute
OpenAlex ID: W2995310662