Inhibiting the Oncogenic Translation Program is an Effective Therapeutic Strategy in Multiple Myeloma

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2017 May 12

PMID 28490664

Citations 44

Authors

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 Jr

Irene M Ghobrial

Affiliations

Soon will be listed here.

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.

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