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

Long, Huideng; Hou, Yue; Li, Jun; Song, Chunhua; Ge, Zheng

doi:10.3390/ijms24076816

Cited by 8 publications

(4 citation statements)

References 58 publications

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“…Furthermore, inhibition of XPO1 expression leads to increased p53 expression, which plays a key role in combination therapy-induced apoptosis ( 51 ). A previous study indicated that selinexor and AZA exert synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling in patients with AML ( 52 ). Accordingly, based on these studies and our clinical findings for the case patient, we hypothesize that the spleen responded synergistically to AZA and selinexor.…”

Section: Discussionmentioning

confidence: 99%

Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine

Liu,

Song,

Dong

et al. 2024

Front. Oncol.

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BackgroundAtypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported.Case descriptionIn this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML.ConclusionOur case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT.

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Section: Discussionmentioning

confidence: 99%

Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine

Liu,

Song,

Dong

et al. 2024

Front. Oncol.

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“…Moreover, in mouse AML models, selinexor was proven to synergize with topoisomerase inhibitors, increase sensitivity to idarubicin, and reduce DNA damage repair [69]. A synergistic anticancer effect with azacitidine was confirmed in AML cell lines [70].…”

Section: Selinexor In Other Hematologic Malignanciesmentioning

confidence: 94%

Selinexor and Other Selective Inhibitors of Nuclear Export (SINEs)—A Novel Approach to Target Hematologic Malignancies and Solid Tumors

Karaszewski,

Jędrzejczak

2023

DDC

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Exportin 1 (XPO1) is a crucial molecule of nucleocytoplasmic transport. Among others, it exports molecules important for oncogenesis from the nucleus to the cytoplasm. The expression of XPO1 is increased in numerous malignancies, which contributes to the abnormal localization of tumor suppressor proteins in the cytoplasm and subsequent cell cycle dysregulation. Selective inhibitors of nuclear export (SINEs) are novel anticancer agents that target XPO1, arrest tumor suppressor proteins in the nucleus, and induce apoptosis in cancer cells. Selinexor, a first-in-class SINE, has already been approved for the treatment of relapsed/refractory multiple myeloma and relapsed/refractory diffuse large B cell lymphoma not otherwise specified. It has also been proven effective in relapsed/refractory and previously untreated acute myeloid leukemia patients. In addition, numerous studies have yielded promising results in other malignancies of the hematopoietic system and solid tumors. However, future clinical use of selinexor and other SINEs may be hampered by their significant toxicity.

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“… 131 , 139 , 144 , 145 , 146 Interestingly, HDAC inhibitor, azacitidine, has also shown to reduce c‐MYC mRNA expression in AML cell lines; combined treatment with Selinexor resulted in synergistically attenuated c‐MYC expression levels and enhanced anti‐leukaemic effects that were partially dependent on the elF4E/c‐MYC/XPO1 axis. 147 …”

Section: Xpo1 Inhibitors In Combination Regimensmentioning

confidence: 99%

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

Newell,

van der Watt,

Leaner

2023

IUBMB Life

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Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose‐limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.

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

Cited by 8 publications

References 58 publications

Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine

Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine

Selinexor and Other Selective Inhibitors of Nuclear Export (SINEs)—A Novel Approach to Target Hematologic Malignancies and Solid Tumors

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

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