TY - JOUR
T1 - The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR
AU - Zhou, Liang
AU - Chen, Shuang
AU - Zhang, Yu
AU - Kmieciak, Maciej
AU - Leng, Yun
AU - Li, Lihong
AU - Lin, Hui
AU - Rizzo, Kathryn A.
AU - Dumur, Catherine I.
AU - Ferreira-Gonzalez, Andrea
AU - Rahmani, Mohamed
AU - Povirk, Lawrence
AU - Chalasani, Sri
AU - Berger, Allison J.
AU - Dai, Yun
AU - Grant, Steven
N1 - Funding Information:
The authors thank Dr Peter D. Aplan (National Institutes of Health [NIH], National Cancer Institute [NCI], Center for Cancer Research) for providing 188G3 and 188NRG-2D cells. This work was supported by the NIH (NCI awards CA93738, CA167708, P50 CA142509, and NCATS UH2 TR001373) and the Leukemia and Lymphoma Society of America (grant R6472). Human tissues, patient consents, clinical data (or other appropriate service) were provided by the Virginia Commonwealth University (VCU) Tissue and Data Acquisition and Analysis Core Facility, supported, in part, with the funding from NIH-NCI Cancer Center Core Support grant P30 CA016059, as well as through the Department of Pathology, School of Medicine, and Massey Cancer Center of VCU. Plasmid preparation was performed at the VCU Macromolecule Core Facility, supported, in part, with funding from NIH-NCI Cancer Center Core grant 5P30CA016059-29. Confocal microscopies were performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, with funding from NIH-National Institute of Neurological Disorders and Stroke Center Core grant 5P30NS047463.
Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34+/CD38-/CD123+ populations, but not normal CD34+ progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy warrants further consideration in AML/MDS, particularly in disease with unfavorable genetic aberrations.
AB - Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34+/CD38-/CD123+ populations, but not normal CD34+ progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy warrants further consideration in AML/MDS, particularly in disease with unfavorable genetic aberrations.
UR - http://www.scopus.com/inward/record.url?scp=84969215491&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-06-653717
DO - 10.1182/blood-2015-06-653717
M3 - Article
C2 - 26851293
AN - SCOPUS:84969215491
SN - 0006-4971
VL - 127
SP - 2219
EP - 2230
JO - Blood
JF - Blood
IS - 18
ER -
