- About half of sporadic meningiomas are null for the neurofibromatosis 2 (NF2) tumor suppressor gene, and this gene deficiency is also a hallmark of neurofibromatosis type 2, a rare disorder that causes multiple types of nervous system tumors
- Massachusetts General Hospital researchers previously showed that NF2 loss leads to aberrant activation of mTORC1/2 signaling, which led to past and ongoing clinical trials with mTOR inhibitors. Follow up studies revealed that combining an mTORC1/2 inhibitor with dasatinib was synergistic in a mouse models of meningioma and vestibular schwannoma
- This study examined the role of neuregulin-1 (NRG1) in the context of NF2 loss in human cell models, finding that NF2 loss leads to NRG1 secretion that in turn activates the ERBB3 receptor kinase in an autocrine fashion
- mTORC1/2 inhibition disrupted NRG1-ERBB3 signaling while increasing pAkt T308, but not pAkt S473, apparently because of an adaptive response involving upregulation of insulin-like growth factor receptor 1/insulin receptor (IGFR1/IR)
- The combination of an mTOR kinase inhibitor and an IGFR1/IR inhibitor had a synergistic effect in human NF2-null meningioma cell lines
About half of sporadic meningiomas, the most common intracranial tumors in adults, are null for the neurofibromatosis 2 (NF2) tumor suppressor gene. NF2 deficiency is also a hallmark of neurofibromatosis type 2 (NF2), a rare disorder that causes multiple types of nervous system tumors, most commonly bilateral vestibular schwannoma (acoustic neuromas) and intracranial meningiomas.
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Even benign meningiomas are apt to cause severe neurologic morbidity and mortality because they compress the adjacent brain or spinal cord. No type of meningioma responds to chemotherapies, and the current standard of care is maximum surgical resection. Clearly, effective pharmacotherapies are sorely needed.
In previous work, researchers at Massachusetts General Hospital demonstrated that NF2 loss led to aberrant activation of mTORC1 and mTORC2 signaling in human arachnoidal cell lines (the cell of origin for meningiomas) and human meningioma cell lines.
Subsequently, the team observed that combining vistusertib, an investigational dual mTORC1/2 inhibitor, with the kinase inhibitor dasatinib was synergistic in a mouse models of meningioma and vestibular schwannoma, as described in Neuro-Oncology and Scientific Reports.
Extending their research, Roberta L. Beauchamp, senior research technologist, and Vijaya Ramesh, PhD, co-director of Mass General Neuroscience and associate neurologist at Massachusetts General Hospital, and colleagues have identified adaptive signaling upon mTOR inhibition in NF2-deficient cells. In the Journal of Biological Chemistry, they give the details and present a rationale for combined inhibition of the mTOR and insulin-like growth factor 1 receptor/insulin receptor (IGF1R/IR) pathways.
High-Throughput Transcriptome Analyses
By analyzing transcriptomic data from their previous studies, the researchers noted increased expression of neuregulin-1 (NRG1), among other ligands, in human arachnoidal and meningioma cells.
NRG1 and its target, the ERBB family of receptors, have been implicated in schwannoma tumorigenesis, and elevated NRG1 expression and activated ERBB3 are seen in many other human cancers. The team decided to focus on studying NRG1–ERBB3 signaling.
- NF2-null cells showed increased NRG1 expression and secretion
- Increased NRG1–ERBB3 signaling activated mTOR signaling pathways in an autocrine loop
Adaptive Response to mTOR Inhibition
- mTORC1 inhibition with rapamycin and mTORC1/2 inhibition with vistusertib significantly downregulated NRG1–ERBB3 signaling
- However, treatment with sapanisertib, another investigational mTORC1/2 inhibitor (alone or combined with the ERBB3 inhibitor seribantumab) disrupted NRG1–ERBB3 signaling while increasing pAkt T308 but not pAkt S473 because of an adaptive response involving upregulation of insulin-like growth factor receptor 1/insulin receptor (IGFR1/IR)
Combination Drug Regimen
The combination of sapanisertib and BMS-754807, an investigational inhibitor of IGF1R/IR family kinases, had a synergistic effect in human immortalized and primary NF2-null meningioma cell lines. These results set the stage for additional in vivo studies of possible novel treatment regimens for NF2-associated tumors.
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