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

doi:10.3389/fonc.2022.910505

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

Front Oncol. 2022 Jul 29:12:910505. doi: 10.3389/fonc.2022.910505. eCollection 2022.

Authors

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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.

Keywords: FAK (focal adhesion kinase); MEK; MPNST; drug resistance; integrins; neurofibromatosis type I.