TY - JOUR
T1 - Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma
AU - Li, Ling
AU - Halpert, Gilad
AU - Lerner, Michael G.
AU - Hu, Haijie
AU - Dimitrion, Peter
AU - Weiss, Matthew J
AU - He, Jin
AU - Philosophe, Benjamin
AU - Burkhart, Richard
AU - Burns, William R.
AU - Wesson, Russell N.
AU - Cameron, Andrew Mac Gregor
AU - Wolfgang, Christopher L.
AU - Georgiades, Christos
AU - Kawamoto, Satomi
AU - Azad, Nilofer S.
AU - Yarchoan, Mark
AU - Meltzer, Stephen J.
AU - Oshima, Kiyoko
AU - Ensign, Laura M.
AU - Bader, Joel S.
AU - Selaru, Florin M.
N1 - Funding Information:
This work was supported by NIH grant R01CA190040 to FMS, by NIH grant U01CA217846 to JSB, and by NIH grant F33CA247344 and Burroughs Wellcome Fund 2019 Collaborative Research Travel Grant 1019964 to MGL.
Publisher Copyright:
© 2021, Li et al.
PY - 2021/6/22
Y1 - 2021/6/22
N2 - Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short-half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report - for the first time to our knowledge - the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.
AB - Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short-half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report - for the first time to our knowledge - the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.
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U2 - 10.1172/jci.insight.138197
DO - 10.1172/jci.insight.138197
M3 - Article
C2 - 34003798
AN - SCOPUS:85108442177
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 12
M1 - e138197
ER -