Targeting Oncogene mRNA Translation in B-Cell Malignancies with eFT226, a Potent and Selective Inhibitor of eIF4A

• Published in: Molecular cancer therapeutics Vol. 20; no. 1; pp. 26 - 36
• Main Authors: Thompson, Peggy A, Eam, Boreth, Young, Nathan P, Fish, Sarah, Chen, Joan, Barrera, Maria, Howard, Haleigh, Sung, Eric, Parra, Ana, Staunton, Jocelyn, Chiang, Gary G, Gerson-Gurwitz, Adina, Wegerski, Christopher J, Nevarez, Andres, Clarine, Jeff, Sperry, Samuel, Xiang, Alan, Nilewski, Christian, Packard, Garrick K, Michels, Theodore, Tran, Chinh, Sprengeler, Paul A, Ernst, Justin T, Reich, Siegfried H, Webster, Kevin R
• Format: Journal Article
• Language: English
• Published: United States 01-01-2021
• Subjects: Animals; Biomarkers, Tumor - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Eukaryotic Initiation Factor-4A - antagonists & inhibitors; Eukaryotic Initiation Factor-4A - metabolism; Female; Humans; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Oncogenes; Protein Biosynthesis - genetics; PTEN Phosphohydrolase - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-19-0973

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5'-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant
efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in
xenograft models. Mutation of PTEN is associated with reduced apoptosis
and diminished efficacy
in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.