The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR
| Autor: | Kathryn A. Rizzo, Steven Grant, Sri Lakshmi Chalasani, Lawrence F. Povirk, Liang Zhou, Yun Dai, Mohamed Rahmani, Allison Berger, Andrea Ferreira-Gonzalez, Lihong Li, Hui Lin, Catherine I. Dumur, Yun Leng, Shuang Chen, Maciej Kmieciak, Yu Zhang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gene knockdown Chemistry DNA repair Immunology Cell Biology Hematology Pharmacology CD38 Biochemistry Small hairpin RNA 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Pevonedistat hemic and lymphatic diseases Cancer research Histone deacetylase CHEK1 Belinostat |
| Zdroj: | Blood. 127:2219-2230 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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