Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex

Abstract

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

Figure 1

Overview of mTOR-TSC regulation and upstream and downstream mediators. Both TSC1 and TSC2 are major components in mTOR signalling cascade. mTOR complexes 1 and 2 (mTORC1 and mTORC2, resp.) are mediators of important cellular functions: mTORC1 (which senses nutrients, energy, growth factors, and stress signals) promotes protein synthesis, cell growth, and cell proliferation, while mTORC2 is associated with cell survival and proliferation. Tuberous sclerosis complex patients present mutations in either TSC1 or TSC2 genes, causing suppression of RHEB-mediated mTORC1 inhibition, exacerbating cell cycle progression, cell proliferation, and growth. Rapamycin (sirolimus) and everolimus are effective inhibitors of mTORC1 via FKBP12.

Figure 2

Molecular structure of sirolimus and its analogues. They all share a central macrolide chemical structure and have a unique R group at the C40 position.