Omacetaxine: A protein translation inhibitor for treatment of chronic myelogenous leukemia

Varsha Gandhi, William Plunkett, Jorge E. Cortes

Research output: Contribution to journalReview article

Abstract

Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein, which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKI) have revolutionized how CML is treated. Although the majority of patients respond to these kinase inhibitors, a subset becomes resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently approved by the U.S. Food and Drug Administration for Philadelphia-positive CML either in the chronic or the accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in the chronic phase and major hematologic response in 27% of patients in the accelerated phase. Laboratory investigations unraveled the mechanismof action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life that makes it susceptible to protein translation inhibitors.Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminutionof short-lived proteins, such as Bcr-Abl, followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.

Original languageEnglish (US)
Pages (from-to)1735-1740
Number of pages6
JournalClinical Cancer Research
Volume20
Issue number7
DOIs
StatePublished - Apr 1 2014
Externally publishedYes

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Protein Biosynthesis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
bcr-abl Fusion Proteins
Genetic Translocation
United States Food and Drug Administration
Ribosomes
Protein Binding
Cytogenetics
Protein-Tyrosine Kinases
Half-Life
Proteins
Cell Death
Phosphotransferases
Therapeutics
Maintenance
homoharringtonine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Omacetaxine : A protein translation inhibitor for treatment of chronic myelogenous leukemia. / Gandhi, Varsha; Plunkett, William; Cortes, Jorge E.

In: Clinical Cancer Research, Vol. 20, No. 7, 01.04.2014, p. 1735-1740.

Research output: Contribution to journalReview article

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