Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma

by Selleckchem | Jul 29 2023

Background: Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies.

Methods: Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2 -/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanism of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models.

Results: Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential.

Conclusions: This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Comments:

Title: The Efficacy of Proteasome Pathway Inhibitors as Potential Novel Therapies for NF2-Associated Tumors

Abstract: Neurofibromatosis 2 (NF2) is an inherited disorder characterized by the inactivation of the NF2 tumor suppressor gene, leading to the development of tumors such as schwannomas and meningiomas. Current treatment options for NF2-associated tumors, including surgery and radiation, are often insufficient due to tumor resistance and recurrence. In this study, we investigated the potential of targeting the ubiquitin-proteasome pathway (UPP) as a novel therapeutic approach for NF2-associated tumors. We performed high-throughput drug screening in NF2 preclinical models and identified a class of compounds that target the UPP. We further evaluated three candidate UPP inhibitors, namely ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243, using human primary and immortalized meningioma cell lines, CRISPR-modified Schwann cells, and mouse Nf2-/- Schwann cells.

Our results demonstrated that ixazomib and TAK-243 exhibited potent reduction in cell viability and induction of apoptosis, whereas pevonedistat did not show the same efficacy. Additionally, we found that ixazomib and TAK-243 downregulated the expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2. Moreover, these inhibitors upregulated genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo studies using orthotopic NF2-deficient meningioma and schwannoma tumor models showed delayed tumor growth following treatment with ixazomib or TAK-243, suggesting their therapeutic potential.

In conclusion, our findings demonstrate the efficacy of proteasome pathway inhibitors, specifically ixazomib and TAK-243, in NF2-associated tumor models. These results provide a strong rationale for further exploration of these drugs as novel treatment strategies for NF2 patients. Targeting the UPP represents a promising avenue for developing cytotoxic therapies that can overcome the resistance observed with traditional treatments for NF2-associated tumors. Further studies are warranted to elucidate the underlying mechanisms and optimize the therapeutic regimens for these inhibitors in the context of NF2.