Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

  • Sci Transl Med. 2017 May 10;9(389):eaal2668. doi: 10.1126/scitranslmed.aal2668.
Salomon Manier  1  2  3 ,  Daisy Huynh  4 ,  Yu J Shen  4 ,  Jia Zhou  4 ,  Timur Yusufzai  4 ,  Karma Z Salem  4 ,  Richard Y Ebright  4 ,  Jiantao Shi  4 ,  Jihye Park  4 ,  Siobhan V Glavey  4 ,  William G Devine  5 ,  Chia-Jen Liu  4 ,  Xavier Leleu  6 ,  Bruno Quesnel  3 ,  Catherine Roche-Lestienne  3 ,  John K Snyder  5 ,  Lauren E Brown  5 ,  Nathanael Gray  4 ,  James Bradner  4 ,  Luke Whitesell  7 ,  John A Porco Jr  5 ,  Irene M Ghobrial  1
Affiliations
  • 1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. [email protected] [email protected].
  • 2. Department of Hematology, Lille Hospital, 59000 Lille, France.
  • 3. INSERM UMR-S 1172, University of Lille 2, 59000 Lille, France.
  • 4. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 5. Boston University Center for Molecular Discovery, Boston, MA 02215, USA.
  • 6. Department of Hematology, University Hospital of Poitiers, 86021 Poitiers, France.
  • 7. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
PMID: 28490664 DOI: 10.1126/scitranslmed.aal2668
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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