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 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.

• Authors: Yihui Gu, Chengjiang Wei, Manhon Chung, Haibo Li, Zizhen Guo, Manmei Long, Yuehua Li, Wei Wang, Rehanguli Aimaier, Qingfeng Li, Zhichao Wang
• Journal: Frontiers in oncology (Front Oncol) Vol. 12 Pg. 910505 ( 2022) ISSN: 2234-943X [Print] Switzerland
• PMID: 35965583 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Gu, Wei, Chung, Li, Guo, Long, Li, Wang, Aimaier, Li and Wang.