Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition

Pu Zhang, Lindsey T. Brinton, Katie Williams, Steven Sher, Shelley Orwick, Lai Tzung-Huei, Alice S. Mims, Christopher C. Coss, Samuel K. Kulp, Youssef Youssef, Wing Keung Chan, Shaneice Mitchell, Allison Mustonen, Matthew Cannon, Hannah Phillips, Amy M. Lehman, Tierney Kauffman, Larry Beaver, Daniel Canfield, Nicole R. GrieselhuberLapo Alinari, Deepa Sampath, Pearlly Yan, John C. Byrd, James S. Blachly, Rosa Lapalombella

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Purpose: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. Experimental Design: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. Results: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT- 9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono- ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemiainitiating cells. Conclusions: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.

Original languageEnglish (US)
Pages (from-to)2352-2366
Number of pages15
JournalClinical Cancer Research
Volume27
Issue number8
DOIs
StatePublished - Apr 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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