| Autor: |
Yihui Gu, Chengjiang Wei, Manhon Chung, Haibo Li, Zizhen Guo, Manmei Long, Yuehua Li, Wei Wang, Rehanguli Aimaier, Qingfeng Li, Zhichao Wang |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Frontiers in Oncology, Vol 12 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2234-943X |
| DOI: |
10.3389/fonc.2022.910505 |
| Popis: |
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas which lack effective drugs. Loss of the RAS GTPase-activating protein NF1 and subsequent overactivation of mitogen-activated protein kinase kinase (MAPK) signaling exist nearly uniformly in MPNST, making MAPK inhibition a promising therapeutic intervention. However, the efficacy of MEK inhibitor (MEKi) monotherapy was limited in MPNST and the relative mechanisms remained largely unexplored. In this study, we generated three MEKi-resistant cell models and investigated the mechanisms of MEKi resistance using high-throughput transcriptomic sequencing. We discovered that cell apoptosis and cell cycle arrest induced by MEKi were rescued in MEKi-resistant cells and the upregulation of LAMA4/ITGB1/FAK/SRC signaling conferred resistance to MEKi. In addition, concurrent inhibition of MAPK signaling and FAK/SRC cascade could sensitize MPNST cells to MEKi. Our findings provide potential solutions to overcome MEKi resistance and effective combination therapeutic strategies for treating MPNSTs. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
