Tuberous sclerosis complex
Genetic disorder from TSC1/TSC2 loss causing constitutive mTOR activation and benign tumors in brain, kidney, and elsewhere, as well as epilepsy, often the presenting problem, and TSC-associated neuropsychiatric disorders. Everolimus shrinks these tumors (EXIST trials) and is also approved for TSC-associated seizures - the clearest randomised human evidence that blocking mTOR helps a human disease driven by mTOR overactivation.
A genetic disease of the pathway's own brake. A genetic disease caused by loss of the TSC1 or TSC2 brake, leaving mTOR stuck in the 'on' position and causing benign tumors in the brain, kidneys, and elsewhere, along with epilepsy, which is often the first sign, and learning and behavior difficulties. Everolimus shrinks these tumors and is approved for the seizures too - the clearest, most direct evidence in humans that blocking mTOR helps a disease actually caused by too much mTOR activity.
The cleanest human demonstration that mTORC1 hyperactivation drives disease, and the setting where rapalogs work best – including on subependymal giant-cell astrocytoma.
TL;DR. Tuberous sclerosis complex appears in 17 curated studies in Oliver's mTOR Atlas: 6 in people (6 human studies); 7 in animal models; 4 at the molecular level (cells, biochemistry, structure). It has 1 interaction in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Everolimus inhibits Tuberous sclerosis complex mechanism: clinical-outcome · this link in full · on the map table | In patients with the genetic disease tuberous sclerosis, everolimus shrank both brain and kidney tumours. It works one step downstream of the mutation: it replaces the brake the mutation removed, so the tumours shrink while the drug is given and regrow when it stops. The mutation itself is untouched. Holds under: Lesions regrow when the drug is stopped - this is suppression, not cure. shown in people · settled in the literature | H | KRU2010, BIS2013, GAO2026B |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 6 |
| A | Animal model | 7 |
| M | Molecular — cells, biochemistry, structure | 4 |
Human studies in the Atlas
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | H | Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial SAX2026 In a multicentre RCT of TSC patients (n=38 randomised, 2:1 everolimus:placebo), 24 weeks of everolimus produced similarly large 'responder' rates for neuropsychological improvement as placebo (87% vs 75%), suggesting large practice/placebo effects rather than a clear drug benefit on cognition -- despite everolimus's established efficacy for TSC tumours and epilepsy. Adverse events were more frequent with everolimus (88% vs 61.5%). |
| 2026 | H | Tumor fat composition predicts response to everolimus and supports low-dose therapy in TSC-associated renal angiomyolipomas: a multicenter prospective study GAO2026B In a multicenter prospective cohort of 183 TSC-associated renal angiomyolipoma patients, everolimus reduced tumor volume by >=50% in 44% of patients at 3 months and 83% at 6 months; fat-poor lesions responded significantly better than fat-rich ones. No significant difference in response was detected between the low-dose and standard-dose groups in an exploratory, non-randomised subset, and oral mucositis was less frequent on the low dose; tumor regrowth occurred after treatment discontinuation. |
| 2016 | H | Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study FRE2016 EXIST-3 was a phase 3, double-blind trial in 366 patients aged 2 to 65 with tuberous sclerosis complex and focal seizures that had not responded to standard drugs. They were randomised 1:1:1 to placebo (n=119), everolimus dosed to a low blood trough of 3-7 ng/mL (n=117) or a high trough of 9-15 ng/mL (n=130), added to their existing antiepileptic drugs. For the primary endpoint, at least a 50% fall in seizure frequency during the 12-week maintenance period, the response rate was 15.1% with placebo, 28.2% with low exposure (p=0.0077) and 40.0% with high exposure (p<0.0001); median seizure reduction was 14.9%, 29.3% and 39.6%. Grade 3-4 adverse events occurred in 11%, 18% and 24%, and serious adverse events in 3%, 14% and 14% of patients, respectively. The result showed a dose-dependent effect of mTOR inhibition on seizures in TSC, beyond its known effect on TSC tumours. Boundary: patients with TSC and treatment-resistant focal-onset seizures already on 1-3 antiepileptic drugs; comparator was placebo add-on; 18-week core phase (6-week titration, 12-week maintenance), so long-term durability is not addressed here. |
| 2013 | H | Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial FRA2013 Phase 3 RCT (n=117) in tuberous sclerosis, the disease where mTOR is stuck ON by a genetic fault. Everolimus shrank brain tumors (SEGA) by >=50% in 35% of patients versus 0% on placebo. Because the underlying cause here is direct mTOR overactivation, this is arguably the cleanest randomised human evidence that blocking mTOR works in a genetically defined mTORopathy -- which does not extend to mTOR inhibition in people without such a mutation. |
| 2013 | H | Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial BIS2013 The companion phase 3 RCT (n=118) to EXIST-1, targeting kidney tumors (angiomyolipomas) in tuberous sclerosis and LAM. Everolimus shrank them by >=50% in 42% of patients versus 0% on placebo. Together EXIST-1 and -2 sealed everolimus as a disease-modifying therapy across multiple TSC tumor types. |
| 2006 | H | Rapamycin causes regression of astrocytomas in tuberous sclerosis complex FRA2006 Five people with tuberous sclerosis complex whose brain astrocytomas were growing on serial scans (four subependymal giant cell astrocytomas, one pilocytic astrocytoma) were treated with oral rapamycin at standard immunosuppressive levels (blood 5-15 ng/ml) for 2.5 to 20 months. On MRI, every lesion shrank, and one showed necrosis. In one patient the tumour grew back when treatment was interrupted and shrank again when it was restarted. Treatment was well tolerated. This small uncontrolled series was one of the early reports that mTOR inhibition can shrink TSC brain tumours in patients, and it preceded the EXIST-1 everolimus trial. Boundary: 5 patients, open-label case series without a control group; TSC-associated astrocytomas only; regression depended on continued treatment. |
| 2026 | A | Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis FER2026 Using kidney-specific mouse models that genetically uncouple mTORC1 activity from TFEB/TFE3 activity (Depdc5-KO, RagC-KO, and Flcn/RagC double-KO), the authors show mTORC1 hyperactivation -- not TFEB/TFE3 activation alone -- is the primary driver of kidney cystogenesis and tumorigenesis in Birt-Hogg-Dube and Tuberous Sclerosis Complex models. Constitutive TFEB/TFE3 activity further accelerates disease on top of mTORC1-driven pathology. |
| 2017 | A | Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy LIP2017 In mouse models of tuberous sclerosis, where mTOR is stuck on, the circadian clock ran abnormally: poor timekeeping in constant conditions and exaggerated responses to phase resetting. mTOR raised BMAL1 levels by changing its translation, degradation and location; genetically lowering BMAL1 rescued the behavioural rhythm defects. Constant, unpatterned mTOR activity disturbs a rhythm downstream. |
| 2012 | A | Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice TSA2012 Deleting one or both copies of Tsc1 only in cerebellar Purkinje cells raised phospho-S6 (a readout of mTORC1) in those cells. Both heterozygous and homozygous mutants showed autism-like behaviour: no preference for a mouse over an object or for a new mouse, more self-grooming, more pup ultrasonic calls and poorer reversal learning in a water T-maze. Purkinje cells fired fewer action potentials, both spontaneously and when driven, in a gene-dose-dependent way, while their synaptic inputs looked largely normal; homozygous mutants also lost Purkinje cells from about 2 months of age and became ataxic. Rapamycin (6 mg/kg intraperitoneally, three times a week from postnatal day 7) prevented the Purkinje cell loss and enlargement and the social, learning and motor deficits. Boundary: mouse, cell-type-specific genetic deletion; rapamycin given from early postnatal life, so this is prevention, not reversal; relevance to human autism is by analogy with TSC patients. |
| 2008 | A | Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function MEI2008 mTOR inhibition rescues a neuronal tuberous-sclerosis model, supporting rapamycin for TSC neurology. |
| 2008 | A | Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis EHN2008 Rapamycin reverses learning and memory deficits in a Tsc2+/- tuberous sclerosis model. |
| 2008 | A | Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex ZEN2008 Mice lacking Tsc1 mainly in glial cells (Tsc1 GFAP conditional knockout) develop glial overgrowth, progressive epilepsy and early death. Rapamycin started at postnatal day 14, before symptoms, prevented epilepsy and premature death; started at 6 weeks, after seizures had begun, it suppressed seizures and prolonged survival. In the brain, rapamycin reversed the abnormal mTOR pathway activation (measured as phospho-S6), the astrogliosis and the neuronal disorganisation, and increased brain size, compared with vehicle-treated knockouts. The study provided evidence in mice that mTOR inhibition can act on epilepsy itself in TSC, not only on tumours, and it is part of the rationale for the later EXIST-3 seizure trial in patients. Boundary: mouse model with Tsc1 deleted mainly in glia, not the human germline mutation; seizure and survival outcomes in mice only; abstract does not state dose or schedule. |
| 2002 | A | A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells KWI2002 The authors built a Tsc1 knockout mouse to model tuberous sclerosis. Embryos lacking both copies of Tsc1 died at mid-gestation because the liver failed to develop. Mice with one copy often developed kidney cystadenomas and liver hemangiomas; the hemangiomas were more common, more severe and more often fatal in females. Fibroblasts lacking Tsc1 showed persistent phosphorylation of S6K and its substrate S6 that rapamycin could reverse, and S6 phosphorylation was also high in kidney tumours from the mice. The authors suggested that blocking this pathway might help control TSC tumours. Boundary: mouse model and mouse cells; the rapamycin result is in cultured cells, and treatment of the mouse tumours was not tested here. |
| 2026 | M | mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis LI2026C Using human brain organoids carrying TSC2 loss-of-function mutations plus patient-derived cortical tuber tissue, shows that hyperactive mTORC1 signaling drives neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell-autonomous manner (downregulated glutamate transporters, elevated inflammatory cytokines and AD-risk genes APOE/CLU) — independent of seizure activity. Positions glial dysfunction as a primary driver of TSC pathology, not merely a downstream consequence. |
| 2024 | M | mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction JOS2024 mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome. |
| 2013 | M | Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis BAT2013 Deleting Tsc1 from cultured mouse hippocampal neurons raised phospho-S6 and made the network fire more than twice as much as controls by day 14, in an epilepsy-like bursting pattern; four days of rapamycin brought activity back to control levels. Many gene-expression and synaptic changes in the knockout cultures, such as high Arc and fewer surface AMPA receptors, turned out to be secondary responses to the high activity, not direct effects of mTOR. In hippocampal CA1, Tsc1 loss in single pyramidal neurons weakened the inhibitory synaptic input they received and raised their excitation/inhibition ratio, while their intrinsic excitability was lower, not higher. Forebrain Tsc1 knockout mice had more severe kainate-induced seizures (80% died, while all controls survived), and seven days of rapamycin in vivo restored inhibition and normalised the E/I ratio. Boundary: mouse neurons, cultures and brain slices; Tsc1 deleted in excitatory neurons only; seizure test used a chemical convulsant. |
| 2005 | M | Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis MA2005 The MAPK input to mTORC1. In mammalian cells, ERK phosphorylates TSC2 and inactivates the TSC complex, so growth signalling through Ras/ERK converges on the same brake that Akt releases. This is the third major upstream arm alongside PI3K/Akt and AMPK. Its practical significance is that it offers a route to mTORC1 activation that PI3K inhibitors do not close - though that inference is mechanistic; no human data here. |
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