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

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 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.

Deacetylation of YAP1 Promotes the Resistance to Chemo- and Targeted Therapy in FLT3-ITD+ AML Cells

“…It has currently emerged as a promising therapeutic strategy for cancer therapy. Indeed, HDAC inhibitors have shown an ability to induce differentiation and apoptosis in AML ( San José-Enériz et al, 2019 ; Zhang et al, 2021 ), leading to a good alternative for treatment, especially for those AML patients not suitable for intensive chemotherapy ( Lübbert et al, 2020 ). Here, we reported that chidamide, a selective HDAC10 inhibitor, combined with FLT3 inhibitors or traditional chemotherapy drugs showed a synergic effect on apoptosis enhancement in the acquired resistant FLT3-ITD + AML cells.…”

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

“…There are many combined treatment strategies for synthetic lethality, and we have selected several representative examples for discussion and summary in Table 15 . 442 – 444 …”

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

“…ACY-241, a second-generation HDAC6 selective inhibitor, has been studied in combination with various agents in multiple cancers such as paclitaxel in solid tumor models; anti-PD-L1, pomalidomide, and daratumumab in multiple myeloma (MM); JQ1 in head and neck cancer; nivolumab in advanced non-small cell lung cancer; and erlotinib in pancreatic cancer [ 18 , 19 , 20 , 21 , 22 , 23 , 55 ]. On the other hand, the HDAC8 selective inhibitor, PCI-34051, has been shown to be effective when treated with KPT-2974 or cytarabine in acute myeloid leukemia and crizotinib or retinoic acid in neuroblastoma [ 56 , 57 , 58 , 59 ]. Although various studies have revealed synergistic anti-cancer effects when using HDACis with chemotherapeutic agents, therapeutic strategies targeting two epigenetic modulators have not been thoroughly investigated.…”