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RNA Polymerase I Inhibition with CX‐5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma
Author(s) -
Lee Hans C.,
Wang Hua,
Baladandayuthapani Veerabhadran,
Lin Heather,
He Jin,
Jones Richard J.,
Kuiatse Isere,
Gu Dongmin,
Wang Zhiqiang,
Ma Wencai,
Lim John,
O'Brien Sean,
Keats Jonathan,
Yang Jing,
Davis Richard E.,
Orlowski Robert Z.
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14525
Subject(s) - cancer research , nucleolin , biology , ribosomal protein , gene silencing , ribosome biogenesis , microbiology and biotechnology , cell growth , cell culture , gene , rna , genetics , ribosome , nucleolus , cytoplasm
Summary 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 TP 53 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 TP 53‐independent mechanisms of CX ‐5461, gene expression profiling was performed on isogenic TP 53 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 TARBP 2 and AGO 2, the ribosomal protein RPL 5, 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.