Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition.

Autor:	Zhang P; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.; College of Pharmacy, The Ohio State University, Columbus, Ohio., Brinton LT; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Williams K; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Sher S; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Orwick S; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Tzung-Huei L; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Mims AS; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Coss CC; College of Pharmacy, The Ohio State University, Columbus, Ohio., Kulp SK; College of Pharmacy, The Ohio State University, Columbus, Ohio., Youssef Y; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Chan WK; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Mitchell S; Department of Pathology, Stanford University School of Medicine, Stanford, California., Mustonen A; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Cannon M; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Phillips H; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Lehman AM; Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio., Kauffman T; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Beaver L; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Canfield D; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Grieselhuber NR; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Alinari L; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Sampath D; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Yan P; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Byrd JC; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.; College of Pharmacy, The Ohio State University, Columbus, Ohio., Blachly JS; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio., Lapalombella R; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. rosa.lapalombella@osumc.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Apr 15; Vol. 27 (8), pp. 2352-2366. Date of Electronic Publication: 2021 Feb 04.
DOI:	10.1158/1078-0432.CCR-20-3724
Abstrakt:	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 leukemia-initiating 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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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