ArticleNeuro-oncology2017
The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity.
Article in Neuro-oncology, 2017. 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, 22 citations in OpenAlex.
- Targeting the Lin28/let-7 Axis with Compounds to Regulate Transcriptional Control in Cancer.Anti-cancer agents in medicinal chemistry · 2026Review
- Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.Human molecular genetics · 2023Article
- Dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating Obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors.Cell death & disease · 2022Article
- Current and Emerging Therapeutic Approaches for Extracranial Malignant Rhabdoid Tumors.Cancer management and research · 2022Review
- TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma.Cancer letters · 2021Article
- Response to letter to the editor: "All models are wrong; some models are useful".Neuro-oncology · 2020Article
- Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors.Neuro-oncology · 2020Article
- MEK Inhibition Suppresses Growth of Atypical Teratoid/Rhabdoid Tumors.Journal of neuropathology and experimental neurology · 2020Article
- Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity.Neuro-oncology · 2020Article
- MEK/MELK inhibition and blood-brain barrier deficiencies in atypical teratoid/rhabdoid tumors.Neuro-oncology · 2020Article
- Atypical Teratoid/Rhabdoid Tumor Originated From the Trigeminal Nerve in a Young Male Adult: Case Report and Review of the Literature.Frontiers in neurology · 2020Article
- Unbiased Metabolic Profiling Predicts Sensitivity of High MYC-Expressing Atypical Teratoid/Rhabdoid Tumors to Glutamine Inhibition with 6-Diazo-5-Oxo-L-Norleucine.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Patient-Derived Orthotopic Xenograft Models of Pediatric Brain Tumors: In a Mature Phase or Still in Its Infancy?Frontiers in oncology · 2019Review
- High LIN28A and PLK4 co‑expression is associated with poor prognosis in epithelial ovarian cancer.Molecular medicine reports · 2018Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundAtypical teratoid/rhabdoid tumors (AT/RTs) are deadly pediatric brain tumors driven by LIN28. Mammalian target of rapamycin (mTOR) is activated in many deadly, drug-resistant cancers and governs important cellular functions such as metabolism and survival. LIN28 regulates mTOR in normal cells. We therefore hypothesized that mTOR is activated downstream of LIN28 in AT/RT, and the brain-penetrating mTOR complex 1 and 2 (mTORC1/2) kinase inhibitor TAK228 would reduce AT/RT tumorigenicity.
methodsActivation of mTOR in AT/RT was determined by measuring pS6 and pAKT (Ser473) by immunohistochemistry on tissue microarray of 18 primary AT/RT tumors. In vitro growth assays (BrdU and MTS), death assays (CC3, c-PARP by western blot), and survival curves of AT/RT orthotopic xenograft models were used to measure the efficacy of TAK228 alone and in combination with cisplatin.
resultsLentiviral short hairpin RNA-mediated knockdown of LIN28A led to decreased mTOR activation. Primary human AT/RT had high levels of pS6 and pAKT (Ser473) in 21% and 87% of tumors by immunohistochemistry. TAK228 slowed cell growth, induced apoptosis in vitro, and nearly doubled median survival of orthotopic xenograft models of AT/RT. TAK228 combined with cisplatin synergistically slowed cell growth and enhanced cisplatin-induced apoptosis. Suppression of AKT sensitized cells to cisplatin-induced apoptosis and forced activation of AKT protected cells. Combined treatment with TAK228 and cisplatin significantly extended survival of orthotopic xenograft models of AT/RT compared with each drug alone.
conclusionsTAK228 has efficacy in AT/RT as a single agent and synergizes with conventional chemotherapies by sensitizing tumors to cisplatin-induced apoptosis. These results suggest TAK228 may be an effective new treatment for AT/RT.
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