Tuberous Sclerosis Complex is an autosomal dominant genetic disease that affects multiple organs in the human body. Lymphangioleiomyomatosis (LAM) is a destructive lung disease that involves the growth of LAM nodules and cyst formation in the airways leading to lung destruction, pneumothorax and chylous pleural effusion. LAM arises primarily in women and progresses more rapidly in premenopausal women than in postmenopausal women. Additional manifestations of TSC include autism, seizures and angiomyolipomas. Importantly, LAM can also occur in women who do not have TSC (sporadic LAM). Sporadic and TSC-associated LAM lesions exhibit loss of function mutations in TSC2 followed by loss of heterozygosity leading to complete loss of TSC2.
Loss of function mutations in TSC1 or TSC2 lead to mTORC1 hyperactivation, which enhances protein translation via downstream targets of mTORC1, including p70 ribosomal S6 kinase, ribosomal protein S6 and 4EBP1. Aberrant mTORC1 activation is known to drive extensive metabolic reprogramming, including glucose and glutamine utilization, enhanced nucleic acid synthesis, lipid synthesis and autophagy. In the clinic, mTORC1 inhibitors (rapalogs) are effective cytostatic agents for the treatment of LAM, leading to the stabilization of lung function. However, lung function continues to deteriorate upon treatment cessation and patients ultimately require lung transplantation. Therefore, we need to identify more durable therapeutic approaches that would ideally elicit a cytotoxic rather than a cytostatic effect against LAM cells.
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