Inhibition MNK‐eIF4E‐β‐catenin preferentially sensitizes gastric cancer to chemotherapy

Yang, Xunzhe; Zhenyang, Liu; Yin, Xi; Zeng, Ying‐Jie; Guo, Geyang

doi:10.1111/fcp.12759

Cited by 7 publications

(10 citation statements)

References 35 publications

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“…In agreement with previous studies that anti-cancer therapies activate eIF4E via increasing eIF4E phosphorylation at S209 in many types of cancer cells and this process can be diminished by MKN inhibitor [15,[18][19][20][21][22], we observed the same in glioblastoma cells after temozolomide treatment. This suggests that MNK/eIF4E is likely to be a potential sensitizing target to overcome temozolomide resistance in glioblastoma.…”

Section: Discussionsupporting

confidence: 93%

Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy

Zhang

Zhao

2023

Fundamemntal Clinical Pharma

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Glioblastoma is characterized by extensive vascularization and is highly resistant to current therapy. Identification of drugs that target tumor directly and angiogenesis processes present an effective therapeutic strategy for glioblastoma. Mnk kinase is required for the activation of eukaryotic initiation factor 4E (eIF4E), which mediates translation of oncogenic proteins. We investigated the effects of tomivosertib, a novel MAPK-interacting kinase (MNK) inhibitor, on glioblastoma angiogenesis, growth, and survival. We found that tomivosertib inhibited growth and induced caspase-dependent apoptosis in various glioblastoma cell lines. Tomivosertib disrupted glioblastoma endothelial cell capillary network formation, growth, and survival. Mechanistically, tomivosertib acted on glioblastoma via suppressing MNKdependent eIF4E phosphorylation and activation in tumor and endothelial cells. We further found that temozolomide activated eIF4E and this was reversed by tomivosertib. Using glioblastoma xenograft mouse model, we demonstrated that temozolomide and tomivosertib combination had higher efficacy than tomivosertib alone. Of note, tomivosertib inhibited glioblastoma angiogenesis and decreased p-eIF4E level in mice. We finally showed that p-eIF4E activation was a common molecular feature in glioblastoma patients. Our pre-clinical findings suggest that tomivosertib is a useful addition to the treatment armamentarium for glioblastoma and that targeting MNK-eIF4E pathway represents a therapeutic strategy to overcome glioblastoma chemoresistance.

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Section: Discussionsupporting

confidence: 93%

Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy

Zhang

Zhao

2023

Fundamemntal Clinical Pharma

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“…15 In addition, eFT508 preferentially sensitizes gastric cancer to chemotherapy. 19 Synergistic effect of eFT-508 and Adriamycin were reported in breast tumor xenografts. 20 It is worthy of evaluating the combinatory effects of eFT508 with chemotherapy in osteosarcoma patient-derived xenograft mouse models.…”

Section: Discussionmentioning

confidence: 99%

MAPK-interacting kinases inhibition by eFT508 overcomes chemoresistance in preclinical model of osteosarcoma

Huang

Jin

et al. 2023

Hum Exp Toxicol

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The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for many cancers with little known in osteosarcoma. This study evaluated the efficacy of eFT508, a highly selective inhibitor of MNK1/2, as single drug alone and in combination with paclitaxel in preclinical models of osteosarcoma. EFT508 is active against multiple osteosarcoma cell lines via inhibiting growth, survival and migration. It also demonstrates anti-osteosarcoma selectivity with much less toxicity on normal osteoblastic than osteosarcoma cells. Consistent with in vitro findings, eFT508 at non-toxic dose significantly arrested tumor growth in mice throughout the whole duration of treatment. Mechanistically, eEFT508 is highly effective in blocking eIF4E phosphorylation and eIF4E-mediated protein translation. Combination index shows that eFT508 and paclitaxel is synergistic in osteosarcoma cells. Our findings highlight the therapeutic value of MNK1/2 inhibition and suggest eFT508 as a promising candidate for the treatment of osteosarcoma.

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“… 81 , 82 Additionally, in gastric cancer, combining tomivosertib with 5-FU or paclitaxel showed benefits in vitro and in vivo, indicating a potential for this MNK inhibitor to sensitize gastric cancer cells to chemotherapy drugs. 83 Similarly, in cervical cancer, combination of cercosporamide with chemotherapy drugs, doxorubicin and cisplatin, had increased efficacy in proliferation reduction and apoptosis induction; cercosporamide inhibited chemo-resistant cells and phosphorylation of eIF4E at serine 209 was shown to be induced with chemotherapy treatment. 84 In AML, MNK inhibitors have similarly been shown to sensitize cells to the chemotherapy drug cytarabine.…”

Section: Preclinical Combination Studies Using Mnk Inhibitorsmentioning

confidence: 99%

MNK Proteins as Therapeutic Targets in Leukemia

Mazewski¹,

Platanias²

2023

OTT

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In leukemia, resistance to therapy is a major concern for survival. MAPK-interacting kinases (MNKs) have been identified as important activators of oncogenic-related signaling and may be mediators of resistance. Recent studies in leukemia models, especially acute myeloid leukemia (AML), have focused on targeting MNKs together with other inhibitors or treating chemotherapy-resistant cells with MNK inhibitors. The preclinical demonstrations of the efficacy of MNK inhibitors in these combination formats would suggest a promising potential for use in clinical trials. Optimizing MNK inhibitors and testing in leukemia models is actively being pursued and may have important implications for the future. These studies are furthering the understanding of the mechanisms of MNKs in cancer which could translate to clinical studies.

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Inhibition MNK‐eIF4E‐β‐catenin preferentially sensitizes gastric cancer to chemotherapy

Cited by 7 publications

References 35 publications

Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy

Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy

MAPK-interacting kinases inhibition by eFT508 overcomes chemoresistance in preclinical model of osteosarcoma

MNK Proteins as Therapeutic Targets in Leukemia

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