Abstract
Meningiomas are the most frequent primary tumors arising in the central nervous system. They typically follow a benign course, with an excellent prognosis for grade I lesions through surgical intervention. Although radiotherapy is a good option for recurrent, progressive, or inoperable tumors, alternative treatments are very limited. mTOR is a protein complex with increasing therapeutical potential as a target in cancer. The current understanding of the mTOR pathway heavily involves it in the development of meningioma. Its activation is strongly dependent on PI3K/Akt signaling and the merlin protein. Both factors are commonly defective in meningioma cells, which indicates their likely function in tumor growth. Furthermore, regarding molecular tumorigenesis, the kinase activity of the mTORC1 complex inhibits many components of the autophagosome, such as the ULK1 or Beclin complexes. mTOR contributes to redox homeostasis, a vital component of neoplasia. Recent clinical trials have investigated novel chemotherapeutic agents for mTOR inhibition, showing promising results in resistant or recurrent meningiomas.
Highlights
70,000 brain tumors are diagnosed each year in the United States, of which meningiomas are the most frequent, accounting for 36% of adult tumors [1]
The strongest evidence links it with the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway through PIP3, which has been shown to activate the mTOR Complex 2 (mTORC2) complex via an indirect pathway
The mTORC1 complex appears to be a critical inhibitor of the formation of autophagosomes through the regulation at many stages of the activation pathway. This function ties into the role of mTOR with the redox homeostasis of meningioma cells
Summary
70,000 brain tumors are diagnosed each year in the United States, of which meningiomas are the most frequent, accounting for 36% of adult tumors [1]. Grade II and III meningiomas are more aggressive and exhibit higher recurrence rates of 50% and 80%, respectively [5]. Such cases may require secondary surgeries which are associated with significant complication rates. The protein kinase forms the core catalytic component of two protein complexes, mTORC1 and mTORC2 Both complexes share this core component, they possess a unique subunit composition and differ in their subcellular localization, substrate binding, and regulation [12]. Two noteworthy genes include the loss of NF2 and mutations in Akt, an important component of the PI3K/Akt pathway Both mechanisms have been shown to activate the mTORC1 complex independently of one another [19,20]
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