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 - 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
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 12
M1 - e138197
ER -