Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma
Files
Accepted manuscript
Date
2017-05-10
Authors
Manier, Salomon
Huynh, Daisy
Shen, Yu J.
Zhou, Jia
Yusufzai, Timur
Salem, Karma Z.
Ebright, Richard Y.
Shi, Jiantao
Park, Jihye
Glavey, Siobhan V.
Version
OA Version
Citation
Salomon Manier, Daisy Huynh, Yu J Shen, Jia Zhou, Timur Yusufzai, Karma Z Salem, Richard Y Ebright, Jiantao Shi, Jihye Park, Siobhan V Glavey, William G Devine, Chia-Jen Liu, Xavier Leleu, Bruno Quesnel, Catherine Roche-Lestienne, John K Snyder, Lauren E Brown, Nathanael Gray, James Bradner, Luke Whitesell, John A Porco, Irene M Ghobrial. 2017. "Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma." Science Translational Medicine [19466234], Volume 9, Issue 389,
Abstract
Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.
Description
Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.