ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2019
The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non-Small Cell Lung Cancer.
Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 28 citations in OpenAlex.
- Loss of PIK3CA AllowsCells · 2026Article
- Loss of PIK3CA allowsbioRxiv : the preprint server for biology · 2026Article
- Antitumor Activity of Isalpinin fromMolecules (Basel, Switzerland) · 2025Article
- Antitumor effects and mechanisms of traditional Chinese medicine gamboge: A review.Frontiers in pharmacology · 2025Review
- Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers.Frontiers in oncology · 2023Article
- Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.Oncology reports · 2022Article
- LKB1 alleviates high glucose‑ and high fat‑induced inflammation and the expression of GnRH and sexual precocity‑related genes, in mouse hypothalamic cells by activating the AMPK/FOXO1 signaling pathway.Molecular medicine reports · 2022Article
- Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado.Molecular cancer research : MCR · 2022Article
- LKB1: Can We Target an Hidden Target? Focus on NSCLC.Frontiers in oncology · 2022Review
- MicroRNA-106a-5p promotes the proliferation, autophagy and migration of lung adenocarcinoma cells by targeting LKB1/AMPK.Experimental and therapeutic medicine · 2021Article
- Rapamycin and trametinib: a rational combination for treatment of NSCLC.International journal of biological sciences · 2021Article
- Predicting Tumor Cell Response to Synergistic Drug Combinations Using a Novel Simplified Deep Learning Model.AMIA ... Annual Symposium proceedings. AMIA Symposium · 2020Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
introductionLiver kinase B1 (LKB1), also called serine/threonine kinase 11 (STK11), is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Approximately 30% to 35% of patients with NSCLC possess inactivated liver kinase B1 gene (LKB1), and these patients respond poorly to anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy. Therefore, novel therapies targeting NSCLC with LKB1 loss are needed.
methodsWe used a new in silico signaling analysis method to identify the potential therapeutic targets and reposition drugs by integrating gene expression data with the Kyoto Encyclopedia of Genes and Genomes signaling pathways. LKB1 wild-type and LKB1-deficient NSCLC cell lines, including knockout clones generated by clustered regularly interspaced short pallindromic repeats-Cas9, were treated with inhibitors of mechanistic target of rapamycin kinase (mTOR) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and a dual inhibitor.
resultsIn silico experiments showed that inhibition of both mTOR and PI3K can be synergistically effective in LKB1-deficient NSCLC. In vitro and in vivo experiments showed the synergistic effect of mTOR inhibition and PI3K inhibition in LKB1-mutant NSCLC cell lines. The sensitivity to dual inhibition of mTOR and PI3K is higher in LKB1-mutant cell lines than in wild-type cell lines. A higher compensatory increase in Akt phosphorylation after rapamycin treatment of LKB1-deficient cells than after rapamycin treatment of LKB1 wild-type cells is responsible for the synergistic effect of mTOR and PI3K inhibition. Dual inhibition of mTOR and PI3K resulted in a greater decrease in protein expression of cell cycle-regulating proteins in LKB1 knockout cells than in LKB1 wild-type cells.
conclusionDual molecular targeted therapy for mTOR and PI3K may be a promising therapeutic strategy in the specific population of patients with lung cancer with LKB1 loss.
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