ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2020
Role of mTOR As an Essential Kinase in SCLC.
Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.
- A multiplexed in vivo approach to identify driver genes in small cell lung cancer.Cell reports · 2023Pooled it
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- Current and future therapies for small cell lung carcinoma.Journal of hematology & oncology · 2025Review
- Transitioning to a Personalized Approach in Molecularly Subtyped Small-Cell Lung Cancer (SCLC).International journal of molecular sciences · 2024Review
- Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma.Molecular cancer research : MCR · 2024Article
- Gastrointestinal stromal tumor with small cell carcinoma infiltration: a case report.Frontiers in oncology · 2024Article
- mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.JCI insight · 2023Article
- AntigeneCancers · 2023Article
- A novel analytical framework for risk stratification of real-world data using machine learning: A small cell lung cancer study.Clinical and translational science · 2022Article
- Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy.Cancer research · 2022Article
- Progression and metastasis of small cell lung carcinoma: the role of the PI3K/Akt/mTOR pathway and metabolic alterations.Cancer metastasis reviews · 2021Review
- Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas.Genes & development · 2021Article
- Small-cell lung cancer.Nature reviews. Disease primers · 2021Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 1 country.
Funding
Abstract
objectivesSCLC represents 15% of all lung cancer diagnoses in the United States and has a particularly poor prognosis. We hypothesized that kinases regulating SCLC survival pathways represent therapeutically targetable vulnerabilities whose inhibition may improve SCLC outcome.
methodsA short-hairpin RNA (shRNA) library targeting all human kinases was introduced in seven chemonaive patient-derived xenografts (PDX) and the cells were cultured in vitro and in vivo. On harvest, lost or depleted shRNAs were considered as regulating-cell survival pathways and deemed essential kinases.
resultsUnsupervised hierarchical cluster analysis of recovered shRNAs separated the PDXs into two clusters, suggesting kinase-based heterogeneity among the SCLC PDXs. A total of 23 kinases were identified as essential in two or more PDXs, with mechanistic Target of Rapamycin (mTOR) a candidate essential kinase in four. mTOR phosphorylation status correlated with PDX sensitivity to mTOR kinase inhibition, and mTOR inhibition sensitized the PDX to cisplatin and etoposide. In the PDX in which mTOR was defined as essential, mTOR inhibition caused a 43% decrease in tumor volume at 21 days (p < 0.01). Combining mTOR inhibition with cisplatin and etoposide decreased PDX tumor volume 96% compared with cisplatin and etoposide alone at 70 days (p < 0.002). Chemoresistance did not develop with the combination of mTOR inhibition and cisplatin and etoposide in mTOR-essential PDX over 105 days. The prevalence of phospho-mTOR-Ser-2448 in a tissue microarray of chemonaive SCLC was 27%, thus, identifying an important SCLC subtype that might benefit from the addition of mTOR inhibition to standard chemotherapy.
conclusionsThese studies reveal that kinases can define SCLC subgroups, can identify therapeutic vulnerabilities, and can potentially be used to optimize therapeutic approaches. Significance We used functional genomics to identify kinases regulating SCLC survival. mTOR was identified as essential in a subset of PDXs. mTOR inhibition decreased PDX growth, sensitized PDX to cisplatin and etoposide, and prevented chemoresistance.
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