Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex.
Tuberous sclerosis complex (TSC) is a genetic autosomal dominant disorder characterized by benign tumor-like lesions, called hamartomas, in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These hamartomas cause a diverse set of clinical problems based on their location and often result in epilepsy, learning difficulties, and behavioral problems. TSC is caused by mutations within the TSC1 or TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth. In normal cells, TSC1 and TSC2 integrate growth signals and nutrient inputs to downregulate signaling to mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase that controls cell growth and cell survival. The molecular connection between TSC and mTOR led to the clinical use of allosteric mTOR inhibitors (sirolimus and everolimus) for the treatment of TSC. Everolimus is approved for subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC. Sirolimus, though not approved for TSC, has undergone considerable investigation to treat various aspects of the disease. Everolimus and sirolimus selectively inhibit mTOR signaling with similar molecular mechanisms, but with distinct clinical profiles. This review differentiates mTOR inhibitors in TSC while describing the molecular mechanisms, pathogenic mutations, and clinical trial outcomes for managing TSC.
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan (J.P.M.); Department of Pediatrics, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (D.A.K.).
Jeffrey P
JP
MacKeigan
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan (J.P.M.); Department of Pediatrics, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (D.A.K.).
Darcy A
DA
Krueger
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy; D002986:Clinical Trials as Topic; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D018315:Glioma, Subependymal / Q000188:drug therapy; D006801:Humans; D008297:Male; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
everolimus; mammalian target of rapamycin; sirolimus; tuberous sclerosis complex