Inhibition of YAP Sensitizes the Selumetinib Treatment for Neurofibromatosis Type 1 Related Plexiform Neurofibroma

Zhuowei Tian; Yuanhe You; Meng Xiao; Jialiang Liu; Guisong Xu; Chunyue Ma; Zhong Du; Yanan Wang

doi:10.7150/ijms.78386

Inhibition of YAP Sensitizes the Selumetinib Treatment for Neurofibromatosis Type 1 Related Plexiform Neurofibroma

Int J Med Sci. 2023 Jan 1;20(1):125-135. doi: 10.7150/ijms.78386. eCollection 2023.

Authors

Zhuowei Tian^{1

2}, Yuanhe You¹, Meng Xiao^{1

2}, Jialiang Liu³, Guisong Xu¹, Chunyue Ma¹, Zhong Du¹, Yanan Wang¹

Affiliations

¹ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China.
² Department of Oral Maxillofacial-Head and Neck Oncology, Fengcheng Hospital, Shanghai, China.
³ Shanghai Stomatological Hospital, Fudan University, Shanghai 200011, China.

Abstract

Background: Targeted therapy of Neurofibromatosis type 1 (NF1) related plexiform neurofibroma (pNF) aiming at MEK molecule has not demonstrated a convincing result for complete disease inhibition, probably due to other signal pathways crosstalk. Our previous study revealed an increased nuclear translocation of YAP molecule in NF1 related pNF. Herein, we decided to further investigate the therapeutic relations of YAP interference during the MEK treatment against NF1 related pNF. Methods: By means of selumetinib (MEK-inhibitor), RNA-sequencing was firstly performed to identify the changes of signal pathways in pNF Schwann cells, which was probably related to YAP regulation. Nuclear-cytoplasmic fractionation and western blotting were performed to show the intracellular YAP changes under selumetinib treatment. Thirdly, a series of in vitro assays were performed including flow cytometry, CCK-8, and colony/sphere formation under dual treatment of selumetinib and verteporfin (YAP-inhibitor). In addition, Chou-Talalay method was adopted to evaluate the synergistic inhibiting effects of such drug combination. Xenograft study was also used to detect the combining effects in vivo. Results: RNA-sequencing revealed that selumetinib treatment might be associated with the undesirable activation of Hippo pathway in NF1 related pNF tumor cells, which might reduce its pharmaceutic effects. Next, nuclear-cytoplasmic fractionation and further studies demonstrated that selumetinib could promote the nuclear translocation and transcriptional activation of YAP in vitro, which might cause the aforementioned resistance to selumetinib treatment. Additionally, when combined treatments were performed based on verteporfin and selumetinib, synergistic effects were observed on cytotoxicity of NF1 related pNF tumor cells in vitro and in vivo xenograft models. Conclusion: YAP inhibition can effectively sensitize NF1 related pNF tumor cells to selumetinib. Dual targeting of YAP and MEK might be a promising therapeutic strategy for treating NF1 related pNF.

Keywords: Neurofibromatosis type 1; Plexiform neurofibroma; Selumetinib; Targeted therapy; YAP.

MeSH terms

Humans
Mitogen-Activated Protein Kinase Kinases / therapeutic use
Neurofibroma, Plexiform* / drug therapy
Neurofibroma, Plexiform* / pathology
Neurofibromatosis 1* / complications
Neurofibromatosis 1* / drug therapy
Neurofibromatosis 1* / genetics
Verteporfin / pharmacology
Verteporfin / therapeutic use

Substances

AZD 6244
Verteporfin
Mitogen-Activated Protein Kinase Kinases