RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma

Hans C. Lee, Hua Wang, Veerabhadran Baladandayuthapani, Heather Lin, Jin He, Richard J. Jones, Isere Kuiatse, Dongmin Gu, Zhiqiang Wang, Wencai Ma, John Lim, Sean O'Brien, Jonathan Keats, Jing Yang, Richard E. Davis, Robert Z. Orlowski

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.

Original languageEnglish (US)
Pages (from-to)80-94
Number of pages15
JournalBritish Journal of Haematology
Volume177
Issue number1
DOIs
StatePublished - Apr 1 2017

Keywords

  • multiple myeloma
  • myeloma cell lines
  • myeloma therapy
  • oncogenes

ASJC Scopus subject areas

  • Hematology

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