ArticleBlood2016
4EBP1/c-MYC/PUMA and NF-κB/EGR1/BIM pathways underlie cytotoxicity of mTOR dual inhibitors in malignant lymphoid cells.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 55 citations in OpenAlex.
- A phase 2 and pharmacological study of sapanisertib in patients with relapsed and/or refractory acute lymphoblastic leukemia.Cancer medicine · 2023Trial
- QSOX2-Mediated Disulfide Bond Modification Enhances Tumor Stemness and Chemoresistance by Activating TSC2/mTOR/c-Myc Feedback Loop in Esophageal Squamous Cell Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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- Mechanism of action of decitabine in treating acute lymphoblastic leukemia.Frontiers in medicine · 2025Article
- Proapoptotic activity of JNK-sensitive BH3-only proteins underpins ovarian cancer response to replication checkpoint inhibitors.Molecular cancer · 2024Article
- Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.Blood cancer discovery · 2024Article
- Next Generation Sequencing for Potential Regulated Genes and Micro-RNAs of Early Growth Response-1 in the Esophageal Squamous Cell Carcinoma.The protein journal · 2022Article
- Characterization of aNAR cancer · 2021Article
- CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia.Cancer research · 2021Article
- TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia.Blood cancer discovery · 2021Article
- Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax.British journal of cancer · 2021Article
- P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9.Neoplasia (New York, N.Y.) · 2021Article
- T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies.Blood cancer discovery · 2021Review
- Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia.Frontiers in oncology · 2021Article
- Rapamycin and trametinib: a rational combination for treatment of NSCLC.International journal of biological sciences · 2021Article
- Reversal of glucocorticoid resistance in paediatric acute lymphoblastic leukaemia is dependent on restoring BIM expression.British journal of cancer · 2020Article
- Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway.Cancer gene therapy · 2020Article
- Article
- Targeted inhibition of mRNA translation initiation factors as a novel therapeutic strategy for mature B-cell neoplasms.Exploration of targeted anti-tumor therapy · 2020Article
- Herbal formula Yangyinjiedu induces lung cancer cell apoptosis via activation of early growth response 1.Journal of cellular and molecular medicine · 2019Article
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15 authors at 3 institutions in 1 country.
Funding
Abstract
The mammalian target of rapamycin (mTOR), a kinase that regulates proliferation and apoptosis, has been extensively evaluated as a therapeutic target in multiple malignancies. Rapamycin analogs, which partially inhibit mTOR complex 1 (mTORC1), exhibit immunosuppressive and limited antitumor activity, but sometimes activate survival pathways through feedback mechanisms involving mTORC2. Thus, attention has turned to agents targeting both mTOR complexes by binding the mTOR active site. Here we show that disruption of either mTOR-containing complex is toxic to acute lymphocytic leukemia (ALL) cells and identify 2 previously unrecognized pathways leading to this cell death. Inhibition of mTORC1-mediated 4EBP1 phosphorylation leads to decreased expression of c-MYC and subsequent upregulation of the proapoptotic BCL2 family member PUMA, whereas inhibition of mTORC2 results in nuclear factor-κB-mediated expression of the Early Growth Response 1 (EGR1) gene, which encodes a transcription factor that binds and transactivates the proapoptotic BCL2L11 locus encoding BIM. Importantly, 1 or both pathways contribute to death of malignant lymphoid cells after treatment with dual mTORC1/mTORC2 inhibitors. Collectively, these observations not only provide new insight into the survival roles of mTOR in lymphoid malignancies, but also identify alterations that potentially modulate the action of mTOR dual inhibitors in ALL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.