TY - JOUR
T1 - Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition
AU - Zhang, Pu
AU - Brinton, Lindsey T.
AU - Williams, Katie
AU - Sher, Steven
AU - Orwick, Shelley
AU - Tzung-Huei, Lai
AU - Mims, Alice S.
AU - Coss, Christopher C.
AU - Kulp, Samuel K.
AU - Youssef, Youssef
AU - Chan, Wing Keung
AU - Mitchell, Shaneice
AU - Mustonen, Allison
AU - Cannon, Matthew
AU - Phillips, Hannah
AU - Lehman, Amy M.
AU - Kauffman, Tierney
AU - Beaver, Larry
AU - Canfield, Daniel
AU - Grieselhuber, Nicole R.
AU - Alinari, Lapo
AU - Sampath, Deepa
AU - Yan, Pearlly
AU - Byrd, John C.
AU - Blachly, James S.
AU - Lapalombella, Rosa
N1 - Funding Information:
The authors are grateful for the patients and healthy volunteers who provided blood and tissue samples for these studies and to the OSU Comprehensive Cancer Center Leukemia Tissue Bank (supported by the NIH, NCI P30 CA016058) for sample procurement. We also thank Drs. David Lucas and Chis Manning for their help in identification and management of primary AML samples at The Ohio State University Leukemia Tissue Bank. We thank the OSUMC genomics core facility for its help with LC-RNA-seq studies. We are grateful for Dr. Feng Zhang’s laboratory for CRISPR GeCKOv2 library. This work was supported by the NIH, NCI (R35 CA197734 and R01 CA223165), the OSU Comprehensive Cancer Center using the Pelotonia Foundation funds, and further research support to the Byrd laboratory from the Harry Mangurian Foundation and the D. Warren Brown Foundation.
Funding Information:
P. Zhang reports a patent for T2021-096 pending. L.T. Brinton reports grants from NIH during the conduct of the study and personal fees from ZielBio outside the submitted work. S. Orwick reports grants from NIH during the conduct of the study. C.C. Coss reports a patent for method of use for AR-42 pending, licensed, and with royalties paid from Recursion Pharmaceuticals. S.K. Kulp reports being a creator of intellectual property related to AR-42 that was recently licensed by The Ohio State University to Recursion Pharmaceuticals. S. Mitchell reports grants from NIH outside the submitted work. D. Sampath reports grants from NCI during the conduct of the study. J.S. Blachly reports personal fees from AbbVie, AstraZeneca, INNATE Pharma, and KITE Pharma and other from Mingsight Pharmaceuticals outside the submitted work, as well as a patent for leukemia diagnostic device pending to none. R. Lapalombella reports grants from NIH during the conduct of the study, a patent T2021-096 pending, and U.S. provisional patent application no. 63/113,821 filed November 13, 2020 entitled “Methods and compositions for cancer therapy.” No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-20-3724
DO - 10.1158/1078-0432.CCR-20-3724
M3 - Article
C2 - 33542077
AN - SCOPUS:85104347230
SN - 1078-0432
VL - 27
SP - 2352
EP - 2366
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -