1. Academic Validation
  2. Combined Cyclin-Dependent Kinase Inhibition Overcomes MAPK/Extracellular Signal-Regulated Kinase Kinase Inhibitor Resistance in Plexiform Neurofibroma of Neurofibromatosis Type I

Combined Cyclin-Dependent Kinase Inhibition Overcomes MAPK/Extracellular Signal-Regulated Kinase Kinase Inhibitor Resistance in Plexiform Neurofibroma of Neurofibromatosis Type I

  • J Invest Dermatol. 2022 Mar;142(3 Pt A):613-623.e7. doi: 10.1016/j.jid.2021.07.164.
Wei Wang 1 Xi-Wei Cui 1 Yi-Hui Gu 1 Cheng-Jiang Wei 1 Yue-Hua Li 1 Jie-Yi Ren 1 Man-Hon Chung 1 Re-Han-Gu-Li Aimaier 1 Hai-Bing Zhang 2 Qing-Feng Li 1 Zhi-Chao Wang 3
Affiliations

Affiliations

  • 1 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]
Abstract

MAPK/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors (MEKis) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in patients with PNF. We determined the efficacy of six different MEKis for treating PNFs, explored drug resistance mechanisms, and identified potential combination therapies to overcome resistance. By screening drug efficacy among six MEKis in human NF1-deficient PNF cell lines, TAK-733 was found to reduce PNF cell viability the most. We then cultured the TAK-733‒resistant cells and explored the potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors as potential agents for PNFs. Dinaciclib, a cyclin-dependent kinase inhibitor, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability and inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including Survivin and cyclin-dependent kinase 1, to induce Apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient‒derived xenografts mouse models. Therefore, the combination of MEKi and cyclin-dependent kinase inhibitor may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant patients with PNF.

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