Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity

Jennifer S. Carew, Claudia M. Espitia, Weiguo Zhao, Valeria Visconte, Faiz - Anwer, Kevin R. Kelly, Steffan T. Nawrocki

Research output: Contribution to journalArticle

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Abstract

Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression of c-MYC and other key oncogenic factors and also significantly induces histone deacetylase 6 (HDAC6) expression. On the basis of the role of HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting of HDAC6 and BET family proteins may represent a novel approach that yields synergistic antimyeloma activity.Weused genetic and pharmacologic approaches to selectively impair HDAC6 and BET function and evaluated the consequential impact on myeloma pathogenesis. These studies identified HDAC6 upregulation as an efficacy reducing mechanism for BET inhibitors because antagonizing HDAC6 activity synergistically enhanced the activity of JQ1 in a panel of multiple myeloma (MM) cell lines and primary CD1381 cells obtained from patients with MM. The synergy of this therapeutic combination was linked to significant reductions in c-MYC expression and increases in apoptosis induction. Administration of the clinical HDAC6 inhibitor ricolinostat was very well tolerated and significantly augmented the in vivo antimyeloma activity of JQ1. Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2. These data demonstrate that cotargeting of HDAC6 and BET family members is a novel and clinically actionable approach to augment the efficacy of both classes of agents that warrants further investigation.

Original languageEnglish (US)
Pages (from-to)1318-1329
Number of pages12
JournalBlood Advances
Volume3
Issue number8
DOIs
StatePublished - Jan 1 2019

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Histone Deacetylases
Multiple Myeloma
Proteins
Apoptosis
Histone Deacetylase Inhibitors
Up-Regulation
Cell Proliferation
Cell Line

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Carew, J. S., Espitia, C. M., Zhao, W., Visconte, V., Anwer, F. ., Kelly, K. R., & Nawrocki, S. T. (2019). Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity. Blood Advances, 3(8), 1318-1329. https://doi.org/10.1182/bloodadvances.2018026484

Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity. / Carew, Jennifer S.; Espitia, Claudia M.; Zhao, Weiguo; Visconte, Valeria; Anwer, Faiz -; Kelly, Kevin R.; Nawrocki, Steffan T.

In: Blood Advances, Vol. 3, No. 8, 01.01.2019, p. 1318-1329.

Research output: Contribution to journalArticle

Carew, JS, Espitia, CM, Zhao, W, Visconte, V, Anwer, F, Kelly, KR & Nawrocki, ST 2019, 'Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity', Blood Advances, vol. 3, no. 8, pp. 1318-1329. https://doi.org/10.1182/bloodadvances.2018026484
Carew, Jennifer S. ; Espitia, Claudia M. ; Zhao, Weiguo ; Visconte, Valeria ; Anwer, Faiz - ; Kelly, Kevin R. ; Nawrocki, Steffan T. / Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity. In: Blood Advances. 2019 ; Vol. 3, No. 8. pp. 1318-1329.
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