Chapter 16 - Dysregulation of TOR Signaling in Tuberous Sclerosis and Lymphangioleiomyomotosis

Abstract

I. Abstract Activation of the mammalian target of rapamycin complex 1 (mTORC1) has been observed in many human tumors and mTORC1 inhibitors have been approved for the treatment of renal cell carcinoma and other malignancies. The tuberous sclerosis complex (TSC) proteins directly regulate Rheb, a direct activator of TORC1. Therefore, TSC and the related disease, pulmonary lymphangioleiomyomatosis (LAM) have the most direct biochemical link to mTORC1 dysregulation of any known human disease or syndrome, providing a unique window through which the direct impact of mTORC1 activation in humans can be viewed. Yet, despite the direct links between TSC and mTORC1, the relationship between mTORC1 activation and the unusual clinical manifestations of TSC remains largely mysterious. Furthermore, TORC1 inhibition has only a partial impact on tumors in TSC patients, with regrowth following discontinuation. In this chapter, we will review the evidence of mTORC1 activation in LAM and TSC, discuss the impact of mTORC1 inhibition in mouse models of TSC and consider how these preclinical models can guide the interpretation of the clinical studies of mTORC1 inhibitors in humans with TSC and LAM. We will also consider the growing evidence that at least some of the clinical manifestations of TSC may reflect TORC1-indepenent functions of the TSC proteins. Finally, we will discuss future clinical perspectives for TSC and LAM patients, focusing on therapeutic approaches combining mTORC1 inhibitors and agents targeting survival pathways and/or TSC-dependent/mTORC1-independent pathways.