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Mason LD, Chava S, Reddi KK, et al. The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis. Cancers (Basel). 2021;13(21)doi: 10.3390/cancers13215516.
Mason, L. D., Chava, S., Reddi, K. K., & Gupta, R. (2021). The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis. Cancers, 13(21), . https://doi.org/10.3390/cancers13215516
Mason, Lawrence David, et al. "The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis." Cancers vol. 13,21 (2021). doi: https://doi.org/10.3390/cancers13215516
Mason LD, Chava S, Reddi KK, Gupta R. The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis. Cancers (Basel). 2021 Nov 03;13(21). doi: 10.3390/cancers13215516. PMID: 34771678; PMCID: PMC8582741.
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Cancers (Basel). 2021 Nov 03;13(21). doi: 10.3390/cancers13215516.

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis.

Cancers

Lawrence David Mason, Suresh Chava, Kiran Kumar Reddi, Romi Gupta

Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35322, USA.
  2. O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35322, USA.

PMID: 34771678 PMCID: PMC8582741 DOI: 10.3390/cancers13215516

Abstract

Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.

Keywords: bromodomain; chromatin; epigenetic regulators; extracellular matrix; melanoma

References

  1. Trends Mol Med. 2019 Mar;25(3):185-197 - PubMed
  2. Front Mol Biosci. 2020 Jan 31;6:160 - PubMed
  3. Cancer Biother Radiopharm. 2001 Apr;16(2):125-32 - PubMed
  4. BMC Med Genomics. 2008 Apr 28;1:13 - PubMed
  5. Oncotarget. 2017 Aug 3;8(44):78174-78192 - PubMed
  6. Front Oncol. 2020 Jul 22;10:1231 - PubMed
  7. Int J Biochem Cell Biol. 1998 Jun;30(6):647-50 - PubMed
  8. Oncogene. 2012 Sep 27;31(39):4257-65 - PubMed
  9. Mol Cancer. 2020 Apr 27;19(1):79 - PubMed
  10. Expert Opin Investig Drugs. 2017 Dec;26(12):1341-1355 - PubMed
  11. Sci Rep. 2018 Apr 10;8(1):5750 - PubMed
  12. Cold Spring Harb Perspect Biol. 2016 Sep 01;8(9): - PubMed
  13. Transl Oncol. 2020 Apr;13(4):100754 - PubMed
  14. Heredity (Edinb). 2010 Jul;105(1):4-13 - PubMed
  15. Int J Mol Sci. 2018 Oct 04;19(10): - PubMed
  16. Mol Cancer Res. 2008 May;6(5):760-9 - PubMed
  17. Antioxidants (Basel). 2021 Feb 19;10(2): - PubMed
  18. Nat Commun. 2015 Jan 22;6:6051 - PubMed
  19. J Neurochem. 2020 Nov;155(3):300-312 - PubMed
  20. Clin Cancer Res. 2005 Oct 15;11(20):7234-42 - PubMed
  21. NDT Plus. 2011 Aug;4(4):251-2 - PubMed
  22. J Cell Biochem. 2006 Mar 1;97(4):882-92 - PubMed
  23. Clin Cancer Res. 2009 Dec 15;15(24):7471-7478 - PubMed
  24. Curr Signal Transduct Ther. 2013 Dec;8(3):193-202 - PubMed
  25. Integr Cancer Ther. 2018 Dec;17(4):1270-1284 - PubMed
  26. Carcinogenesis. 2010 Jan;31(1):27-36 - PubMed
  27. Onco Targets Ther. 2015 Jun 09;8:1387-98 - PubMed
  28. J Transl Med. 2012 Oct 30;10:215 - PubMed
  29. Front Cell Dev Biol. 2021 May 24;9:659392 - PubMed
  30. NPJ Precis Oncol. 2021 Jun 10;5(1):50 - PubMed
  31. J Immunother Cancer. 2018 Jul 3;6(1):65 - PubMed
  32. J Med Chem. 2020 Mar 26;63(6):3227-3237 - PubMed
  33. J Oncol. 2012;2012:915140 - PubMed
  34. Cancer Gene Ther. 2010 Sep;17(9):599-613 - PubMed
  35. Brief Funct Genomics. 2018 Jan 1;17(1):49-63 - PubMed
  36. Melanoma Res. 2018 Dec;28(6):521-526 - PubMed
  37. J Med Chem. 2017 May 25;60(10):4403-4423 - PubMed
  38. Ther Clin Risk Manag. 2015 Jun 23;11:979-90 - PubMed
  39. Clin Cancer Res. 2000 Aug;6(8):3056-61 - PubMed
  40. Signal Transduct Target Ther. 2021 Apr 23;6(1):153 - PubMed
  41. P T. 2014 Jul;39(7):483-519 - PubMed
  42. Br J Cancer. 2021 Feb;124(4):681-682 - PubMed
  43. Signal Transduct Target Ther. 2019 Dec 17;4:62 - PubMed
  44. Clin Genet. 2012 Apr;81(4):303-11 - PubMed
  45. Drugs. 2018 Apr;78(5):549-566 - PubMed
  46. Nat Genet. 2015 Sep;47(9):996-1002 - PubMed
  47. J Med Life. 2014 Oct-Dec;7(4):572-6 - PubMed
  48. Theranostics. 2020 Sep 15;10(25):11428-11443 - PubMed
  49. Mol Oncol. 2014 Sep 12;8(6):1132-9 - PubMed
  50. Ther Adv Med Oncol. 2016 Jan;8(1):48-56 - PubMed

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