title: RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma.
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.
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Lee
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Lin
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Gu
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wencai
authors.initials: W
authors.lastname: Ma
authors.affiliation: Senhwa Biosciences, Inc., San Diego, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lim
authors.affiliation: Senhwa Biosciences, Inc., San Diego, CA, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Keats
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Davis
authors.affiliation: The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D052160:Benzothiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C557717:CX 5461; D009287:Naphthyridines; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D012318:RNA Polymerase I
keywords: multiple myeloma; myeloma cell lines; myeloma therapy; oncogenes