ArticleOncogene2019
Mechanisms underlying synergy between DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors in NF1-associated malignant peripheral nerve sheath tumors.
Article in Oncogene, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
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- Combinatory anti-tumor activities of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4) and temsirolimus against colorectal cancer cells.Journal of cancer research and clinical oncology · 2023Article
- A platinum@polymer-catechol nanobraker enables radio-immunotherapy for crippling melanoma tumorigenesis, angiogenesis, and radioresistance.Bioactive materials · 2023Article
- Review
- Nicotine Neurotoxicity Involves Low Wnt1 Signaling in Spinal Locomotor Networks of the Postnatal Rodent Spinal Cord.International journal of molecular sciences · 2021Article
- Bioinformatic analysis linking genomic defects to chemosensitivity and mechanism of action.PloS one · 2021Article
- Zebrafish Cancer Predisposition Models.Frontiers in cell and developmental biology · 2021Review
- The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors.Oncogene · 2021Article
- Structural basis of quinolone derivatives, inhibition of type I and II topoisomerases and inquiry into the relevance of bioactivity in odd or even branches with molecular docking study.Journal of molecular structure · 2020Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that frequently arise in patients with neurofibromatosis type 1 (NF1). Most of these tumors are unresectable at diagnosis and minimally responsive to conventional treatment, lending urgency to the identification of new pathway dependencies and drugs with potent antitumor activities. We therefore examined a series of candidate agents for their ability to induce apoptosis in MPNST cells arising in nf1/tp53-deficient zebrafish. In this study, we found that DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors were the most effective single agents in eliminating MPNST cells without prohibitive toxicity. In addition, three members of these classes of drugs, either AZD2014 or INK128 in combination with irinotecan, acted synergistically to induce apoptosis both in vitro and in vivo. In mechanistic studies, irinotecan not only induces apoptosis by eliciting a DNA damage response, but also acts synergistically with AZD2014 to potentiate the hypophosphorylation of 4E-BP1, a downstream target of mTORC1. Profound hypophosphorylation of 4E-BP1 induced by this drug combination causes an arrest of protein synthesis, which potently induces tumor cell apoptosis. Our findings provide a compelling rationale for further in vivo evaluation of the combination of DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors against these aggressive nerve sheath tumors.
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