ReferenceID 1594
Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer
Mol Cancer
EGFR-TKI targeted therapy is one of the most effective treatments for lung cancer patients harboring EGFR activating mutations. However, inhibition response is easily attenuated by drug resistance, which is mainly due to
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- Reference Id
- 1594
- Evidence Id
- 18184
- Core Evidence Id
- 18184
- Source Reference Id
- 3196
- Herb2 Reference Id
- HBREF003993
- Subject Paper Key
- HBIN021599_36203195
- Pubmed Id
- 36203195
- Doi
- 10.1186/s12943-022-01662-1
- Paper Title
- Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer
- Paper Abstract
- EGFR-TKI targeted therapy is one of the most effective treatments for lung cancer patients harboring EGFR activating mutations. However, inhibition response is easily attenuated by drug resistance, which is mainly due to bypass activation or downstream activation. Herein, we established osimertinib-resistant cells by stepwise dose-escalation in vitro and an osimertinib-resistant patient-derived xenograft model through persistent treatment in vivo. Phosphorylated proteomics identified that MEK1 and AKT1/2 were abnormally activated in resistant cells compared with parental cells. Likewise, EGFR inhibition by osimertinib induced activation of MEK1 and AKT1/2, which weakened osimertinib sensitivity in NSCLC cells. Consequently, this study aimed to identify a novel inhibitor which could suppress resistant cell growth by dual targeting of MEK1 and AKT1/2. Based on computational screening, we identified that costunolide could interact with MEK1 and AKT1/2. Further exploration using in vitro kinase assays validated that costunolide inhibited the kinase activity of MEK1 and AKT1/2, which restrained downstream ERK-RSK2 and GSK3β signal transduction and significantly induced cell apoptosis. Remarkably, the combination of osimertinib and costunolide showed synergistic or additive inhibitory effects on tumor growth in osimertinib-resistant cell lines and PDX model. Hence, this study highlights a potential therapeutic strategy for osimertinib-resistant patients through targeting of MEK1 and AKT1/2 by costunolide.
- Journal
- Mol Cancer
- Publish Year
- 2022
- Experiment Subject
- patient; nsclc cells; osimertinib-resistant cell lines; osimertinib-resistant cells; pdx model; resistant cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Lung Cancer; Tumor; Osimertinib-resistant
- Paper Title Cn
- Paper Title En
- Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer
- Bilingual Status
- semi_complete