Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors
Yihui Gu, Chengjiang Wei, Manhon Chung, Haibo Li, Zizhen Guo, Manmei Long, Yuehua Li, Wei Wang, Rehanguli Aimaier, Qingfeng Li, Zhichao Wang
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 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.