Rapamycin and trametinib: a rational combination for treatment of NSCLC
| Autor: | Chao-Yue Sun, Yi-Zhuo Li, Di Cao, Hui-Yun Wang, Yu-Feng Zhou, Mei-Yin Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Lung Neoplasms Pyridones Blotting Western Apoptosis Drug resistance Pyrimidinones Applied Microbiology and Biotechnology Trametinib Carcinoma Non-Small-Cell Lung Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Rapamycin Phosphorylation Lung cancer Extracellular Signal-Regulated MAP Kinases Molecular Biology Protein kinase B Ecology Evolution Behavior and Systematics PI3K/AKT/mTOR pathway Sirolimus Mice Inbred BALB C business.industry Drug Synergism Cell Biology medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Synergy ERK Cancer research mTOR Female business Proto-Oncogene Proteins c-akt Developmental Biology Research Paper |
| Zdroj: | International Journal of Biological Sciences |
| ISSN: | 1449-2288 |
| Popis: | Mammalian target of rapamycin (mTOR) is one of the most commonly activated pathways in human cancers, including lung cancer. Targeting mTOR with molecule inhibitors is considered as a useful therapeutic strategy. However, the results obtained from the clinical trials with the inhibitors so far have not met the original expectations, largely because of the drug resistance. Thus, combined or multiple drug therapy can bring about more favorable clinical outcomes. Here, we found that activation of ERK pathway was responsible for rapamycin drug resistance in non-small-cell lung cancer (NSCLC) cells. Accordingly, rapamycin-resistant NSCLC cells were more sensitive to ERK inhibitor (ERKi), trametinib, and in turn, trametinib-resistant NSCLC cells were also susceptible to rapamycin. Combining rapamycin with trametinib led to a potent synergistic antitumor efficacy, which induced G1-phase cycle arrest and apoptosis. In addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib synergized with other mTORi, Torin1 and OSI-027. Mechanistically, rapamycin in combination with trametinib resulted in a greater decrease of phosphorylation of AKT, ERK, mTOR and 4EBP1. In xenograft mouse model, co-administration of rapamycin and trametinib caused a substantial suppression in tumor growth without obvious drug toxicity. Overall, our study identifies a reasonable combined strategy for treatment of NSCLC. |
| Databáze: | OpenAIRE |
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