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RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma.
Br J Haematol. 2017 04; 177(1):80-94.BJ

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+Show Affiliations

The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Senhwa Biosciences, Inc., San Diego, CA, USA.Senhwa Biosciences, Inc., San Diego, CA, USA.Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28369725

Citation

Lee, Hans C., et al. "RNA Polymerase I Inhibition With CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma." British Journal of Haematology, vol. 177, no. 1, 2017, pp. 80-94.
Lee HC, Wang H, Baladandayuthapani V, et al. RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. Br J Haematol. 2017;177(1):80-94.
Lee, H. C., Wang, H., Baladandayuthapani, V., Lin, H., He, J., Jones, R. J., Kuiatse, I., Gu, D., Wang, Z., Ma, W., Lim, J., O'Brien, S., Keats, J., Yang, J., Davis, R. E., & Orlowski, R. Z. (2017). RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. British Journal of Haematology, 177(1), 80-94. https://doi.org/10.1111/bjh.14525
Lee HC, et al. RNA Polymerase I Inhibition With CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. Br J Haematol. 2017;177(1):80-94. PubMed PMID: 28369725.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. AU - Lee,Hans C, AU - Wang,Hua, AU - Baladandayuthapani,Veerabhadran, AU - Lin,Heather, AU - He,Jin, AU - Jones,Richard J, AU - Kuiatse,Isere, AU - Gu,Dongmin, AU - Wang,Zhiqiang, AU - Ma,Wencai, AU - Lim,John, AU - O'Brien,Sean, AU - Keats,Jonathan, AU - Yang,Jing, AU - Davis,Richard E, AU - Orlowski,Robert Z, PY - 2016/07/04/received PY - 2016/09/12/accepted PY - 2017/4/4/entrez PY - 2017/4/4/pubmed PY - 2017/5/19/medline KW - multiple myeloma KW - myeloma cell lines KW - myeloma therapy KW - oncogenes SP - 80 EP - 94 JF - British journal of haematology JO - Br. J. Haematol. VL - 177 IS - 1 N2 - 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. SN - 1365-2141 UR - https://www.unboundmedicine.com/medline/citation/28369725/RNA_Polymerase_I_Inhibition_with_CX_5461_as_a_Novel_Therapeutic_Strategy_to_Target_MYC_in_Multiple_Myeloma_ L2 - https://doi.org/10.1111/bjh.14525 DB - PRIME DP - Unbound Medicine ER -