The Combination of HSP90 Inhibitors and Selumetinib Reinforces the Inhibitory Effects on Plexiform Neurofibromas

TL;DR

Combining HSP90 inhibitors with selumetinib improves treatment of plexiform neurofibromas in mice and may reduce side effects in patients.

Contribution

A novel combination therapy using HSP90 inhibitors and selumetinib for treating plexiform neurofibromas is proposed and validated.

Findings

Combining SNX-2112 or retaspimycin with selumetinib shows synergistic tumor inhibition in pNF cell lines.

The combination significantly delays tumor progression in mouse models of pNFs.

The therapy reduces the required dosage of selumetinib while maintaining efficacy.

Abstract

Plexiform neurofibromas (pNFs) are common, benign tumors in pediatric patients with Neurofibromatosis type 1 (NF1). Selumetinib, an FDA-approved MEK inhibitor, raises concerns about its long-term side effects. Our drug screen data mining identified a list of heat shock protein 90 inhibitors that can be combined with selumetinib for improved therapeutic efficacy. We tested SNX-2112 or retaspimycin in combination with selumetinib and revealed the potent inhibition and synergistic effects in pNF cell lines. Furthermore, we demonstrated a better inhibitory effect of the combination of SNX-2112 and selumetinib on tumor growth in vivo, using the DhhCreNf1f/f-derived mouse pNFs.

Background/Objectives: Plexiform neurofibromas (pNFs) are one of the cardinal presentations of NF1 patients, often arising during early childhood. Since selumetinib was approved by the FDA in 2020, the long-term side effects and various responses of mitogen-activated protein kinase inhibitors (MEKi) in pediatric patients necessitate a new strategy. We propose that combining selumetinib with heat shock protein 90 inhibitors (HSP90i) can enhance the inhibitory effects as well as reduce the dosage of selumetinib in combination. We validated the synergistic effects and the significantly improved treatment effects of the combination of selumetinib and HSP90i in pNFs. Methods: We used drug screen data mining to predict the combination of selumetinib and HSP90i. Using cell lines and in vivo mouse models for pNFs, we tested a series of combinations with different concentrations. We validated the in vivo inhibitory effects using the transplanted tumors from DhhCreNf1f/f mouse models. Results: We demonstrated that combining selumetinib and SNX-2112 or retaspimycin can achieve better tumor inhibition with synergistic effects. The combination significantly delays the progression of mouse pNFs. Conclusions: The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination.

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