Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors.

ABSTRACT: 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 signali

SUBMITTER: Gu Y 

PROVIDER: S-EPMC9372505 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature