ArticleJCI insight2023
mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- Overcoming mTOR Inhibitor Resistance: From Biological Basis to Therapeutic Strategies.Biomedicines · 2026Review
- Assessment of susceptibility to mTOR rs2295080 gene polymorphism in Guangxi Zhuang lung cancer population.Journal of thoracic disease · 2026Article
- Activating protein kinases to treat diseases: Current understanding and future challenges.Acta pharmaceutica Sinica. B · 2026Review
- The Five-Decade Journey of Small Cell Lung Cancer.Cancer communications (London, England) · 2026Review
- PI3K/AKT/mTOR and PD‑1/CTLA‑4/CD28 pathways as key targets of cancer immunotherapy (Review).Oncology letters · 2024Review
- Review
- Small cells - big issues: biological implications and preclinical advancements in small cell lung cancer.Molecular cancer · 2024Review
- Pathogenic role of super-enhancers as potential therapeutic targets in lung cancer.Frontiers in pharmacology · 2024Review
- Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer.Current cancer drug targets · 2024Review
- DDIT4/mTOR signaling pathway mediates cantharidin-induced hepatotoxicity and cellular damage.Frontiers in pharmacology · 2024Article
- Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets.Cell death discovery · 2023Review
- RSK3 switches cell fate: from stress-induced senescence to malignant progression.Journal of experimental & clinical cancer research : CR · 2023Article
- Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy.Signal transduction and targeted therapy · 2023Review
- Somatic gain-of-function mutations in BUD13 promote oncogenesis by disrupting Fbw7 function.The Journal of experimental medicine · 2023Article
- BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation.Molecular cancer research : MCR · 2023Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment the antitumor activities of BETis in SCLC. We found that multiple drugs targeting the PI-3K-AKT-mTOR pathway synergize with BETis, among which mTOR inhibitors (mTORis) show the highest synergy. Using various molecular subtypes of the xenograft models derived from patients with SCLC, we confirmed that mTOR inhibition potentiates the antitumor activities of BETis in vivo without substantially increasing toxicity. Furthermore, BETis induce apoptosis in both in vitro and in vivo SCLC models, and this antitumor effect is further amplified by combining mTOR inhibition. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway. However, BET inhibition leads to RSK3 upregulation, which promotes survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTORis block this protective signaling and augment the apoptosis induced by BET inhibition. Our findings reveal a critical role of RSK3 induction in tumor survival upon BET inhibition and warrant further evaluation of the combination of mTORis and BETis in patients with SCLC.
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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 OpenQuestion graph.