‘An NF2- wildtype malignant meningioma cell line for basic and translational science’

Background

Meningiomas are the most common primary nervous system neoplasm in adults. There are few good cellular models, especially of high grade/malignant meningiomas, to use to identify new therapeutic agents and treatment regimens. The widely available, partially characterized, NF2- wildtype ( NF2 wt) Grade 3 malignant meningioma cell line IOMM-Lee can help meet this need.

Methods

We generated new data to better characterize IOMM-Lee genomic and mtDNA variants, proliferation rate and colony-forming efficiency and sensitivity to ionizing radiation as a function of ATM kinase activity. A screen of 349 anti-cancer drugs identified multiple, mechanistically distinct clinical use drugs with nanomolar IC ₅₀ values and high drug sensitivity prediction scores.

Results

Exome sequencing confirmed that IOMM-Lee is NF2wt , and contains a pathogenic TERT -promoter (c.-124C>T) variant. Population doubling times (PDT) were short (19-21 hrs), and colony forming efficiency (CFE) high, of up to 87%. IOMM-Lee is comparatively radiosensitive with a D ₁₀ of ∼3.9 Gy, and could be radiosensitized by AZD-1390-mediated ATM kinase inhibition. Thirty-four anti-cancer compounds spanning several mechanistic classes were identified that potently suppressed cell proliferation at sub-micromolar IC ₅₀ values with high Breeze 2.0 Drug Sensitivity Scores.

Importance of the Study

We provide new data to better characterize IOMM-Lee, the most widely used cell line model of human Grade 3 malignant meningioma. These data identify and characterize IOMM-Lee genomic alterations and mtDNA variants; quantify growth kinetics and ionizing radiation sensitivity; and identify multiple mechanistically distinct, clinical use drugs with nanomolar IC ₅₀ values, high drug sensitivity prediction scores and potential as meningioma systemic therapies. Our data more clearly locate IOMM-Lee in the landscape of genomically-defined meningiomas, and will aid better use of this experimentally tractable cell line model to understand meningioma biology and identify more effective malignant meningioma therapies and treatment regimens.

Key points

• IOMM-Lee lacks NF2 mutations, though is clearly related to but distinct from many other meningiomas and meningioma cell lines.

• IOMM-Lee grows rapidly, is comparatively radio-sensitive, and can be suppressed by several mechanistic classes of anti-cancer agents at clinically achievable, sub-micromolar IC ₅₀ values with high Drug Sensitivity Scores.

• The experimental tractability, simplicity and versatility of IOMM-Lee can facilitate analyses of many aspects of meningioma biology and therapeutic development across a wide range of in vitro , high throughput and in vivo xenograft/organoid protocols.