Different mechanisms of drug resistance to hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukemia

Šimoničová, Kristína; Janotka, Ľuboš; Kavcová, Helena; Sulová, Zdena; Breier, Albert; Messingerová, Lucia

doi:10.1016/j.drup.2022.100805

Cited by 29 publications

(21 citation statements)

References 159 publications

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“…AML is a relatively common hematological malignancy characterized by a low survival rate and inadequate available therapies [ 35 , 36 ]. Aberrant DNA methylation is a common feature in AML, and although AZA, a targeted demethylation inhibitor AZA, has been used in AML, some patients do not respond to AZA, and most treatment-responsive patients eventually acquire resistance [ 16 , 37 ]. Targeted therapy has emerged as a promising treatment strategy for chemotherapy-resistant AML, where combinations of venetoclax and DNA methyltransferase inhibitors have proven successful examples [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

Long

Hou

et al. 2023

IJMS

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Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.

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Section: Discussionmentioning

confidence: 99%

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

Long

Hou

et al. 2023

IJMS

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“… 44 Since DAB2IP is not the only gene regulated by DAC, DAC might act as a therapeutic agent for TNBC by affecting multiple pathways. 45 , 46 As we only investigated the effect of DAC on DAB2IP expression, further studies of genomic DNA methylation pattern variations caused by DAC treatment are required to comprehensively elucidate the anticancer effect of DAC in TNBC. Although we used a low dose of DAC, which is reported to be well tolerated, side effects and toxicity (including myelosuppression and asymptomatic increases in platelet counts without micronucleated erythrocytes) are inevitable.…”

Section: Discussionmentioning

confidence: 99%

“…By decreasing DNMT expression, DAC inhibits genomic DNA methylation and induces re‐expression of a series of genes (including DAB2IP) 44 . Since DAB2IP is not the only gene regulated by DAC, DAC might act as a therapeutic agent for TNBC by affecting multiple pathways 45,46 . As we only investigated the effect of DAC on DAB2IP expression, further studies of genomic DNA methylation pattern variations caused by DAC treatment are required to comprehensively elucidate the anticancer effect of DAC in TNBC.…”

Section: Discussionmentioning

confidence: 99%

DAB2IP attenuates chemoresistance of triple‐negative breast cancer through sequestration of RAC1 to prevent β‐catenin nuclear accumulation

Xiong

Yang

et al. 2022

Clinical & Translational Med

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Background Although chemotherapy, the most widely used systemic treatment in triple‐negative breast cancer (TNBC), markedly improved the patients’ outcome, chemoresistance always occurs. This study purposed to explore new therapeutic strategies for the treatment of chemoresistance. Methods and results The expression and prognostic value of DAB2IP were investigated in TNBC tissues and cell lines. Low DAB2IP expression predicted high mortality risk in TNBC. Inhibition of DAB2IP expression conferred cancer stem cell capacity and chemoresistance in TNBC cell lines. Using murine breast cancer (BC) xenograft models, we evaluated the association with DAB2IP and chemoresistance. DAB2IP inhibited TNBC tumourigenesis and chemoresistance in vivo. Further, we revealed that DAB2IP inhibited β‐catenin nuclear transport through competitive interaction with RAC1 and decreased β‐catenin accumulation in the cell nucleus. Finally, we found that the DNA methylation level was negatively associated with DAB2IP expression in TNBC. Inhibition of DNA methylation restored the DAB2IP expression and attenuated chemoresistance in TNBC. Conclusions We revealed that DAB2IP attenuates chemoresistance of TNBC via inhibition of RAC1‐mediated β‐catenin nuclear accumulation. Decitabine treatment results in re‐expression of DAB2IP by inhibiting DNA methylation and could be a potential therapeutic strategy for chemoresistance in TNBC.

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“…Dinaciclib (SCH727965) is an inhibitor of cyclin-dependent kinases (CDKs) 1,2,5 and 9. Deregulation of cell cycle control caused by abnormal CDKs activity is observed in most cancers, including AML (Cucchi et al, 2020;Šimoničová et al, 2022;Grant and Roberts, 2003). Exposure of human leukemic and myeloma cells to nanomolar concentrations of dinaciclib inhibited sXBP-1 nuclear localization and expression of BiP, which are prompted in response to treatment with the ER stress inducers tunicamycin and thapsigargin, increasing their cytotoxic effects (Nguyen and Grant, 2014).…”

Section: Targeting the Upr As A Therapeutic Strategy For Amlmentioning

confidence: 99%

Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia

Śniegocka

Liccardo

Fazi

et al. 2022

Drug Resistance Updates

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Different mechanisms of drug resistance to hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukemia

Cited by 29 publications

References 159 publications

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

DAB2IP attenuates chemoresistance of triple‐negative breast cancer through sequestration of RAC1 to prevent β‐catenin nuclear accumulation

Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia

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