Tumor growth
The shared endpoint of the pathway's oncogenic lesions, and the outcome every mTOR inhibitor trial in this Atlas was actually measuring.
Cancer growing. How much a tumor grows and spreads - the outcome that every mTOR-inhibitor cancer trial in this Atlas was ultimately trying to measure.
Genotype-dependent: mTORC1 activation is a strong dependency in TSC- and PI3K-pathway-mutant contexts and much weaker elsewhere.
TL;DR. Tumor growth appears in 15 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 7 in animal models; 7 at the molecular level (cells, biochemistry, structure). It has 1 interaction in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| mTORC1 activates Tumor growth mechanism: functional-consequence · this link in full · on the map table | In mouse tumour models and cancer cells where the pathway is already over-active, hyperactive mTORC1 pushes cells to build a specific set of growth- and spread-promoting proteins, and the tumour becomes dependent on that programme. Holds under: Context-dependent: shown in genetically driven mouse tumour models and cancer cell lines with hyperactive mTORC1 (PTEN loss, TSC loss), not as a general property of tumours. OKI2021 (mouse AML) is not cited as support: mTORC1 activity fell as the leukaemia progressed and rose during the chemotherapy response, so it bears on when to inhibit mTORC1, not on mTORC1 driving growth. plausible in people, not shown directly · settled in the literature | A | HSI2010, HSI2012, VAL2017, INO2006, FER2026, NES2001, POD2001 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 7 |
| M | Molecular — cells, biochemistry, structure | 7 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2008 | H | Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial MOT2008 Everolimus extended median progression-free survival from 1.9 to 4.0 months versus placebo in metastatic renal cell carcinoma. |
| 2026 | A | mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment NAT2026 In syngeneic TP53-mutant HNSCC mouse models, the mTOR inhibitor everolimus reprogrammed the immune-cold tumor microenvironment: it increased CD8+ T cell and dendritic cell infiltration, reduced Tregs and HIF-1α/VEGFA-driven MDSC recruitment, boosted TNF-α/CXCL10 chemokine signaling, and reduced PD-1/PD-L1 expression — restoring T-cell cytotoxic competence and suppressing tumor growth. |
| 2026 | A | Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma. ZHANG2026 TSC1 loss drives non-canonical mTORC1-mediated TFEB nuclear translocation, promoting hepatocyte-to-biliary plasticity and spontaneous aggressive HCC in mice; Tsc1/Tfeb double knockout rescues the phenotype. |
| 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. |
| 2021 | A | Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML OKI2021 Fluorescent probes imaged in the bone marrow of live mice show mTORC1 activity in AML cells falls as the disease progresses but is high at the moment of maximal chemotherapy response, where it is induced rather than selected; inhibiting mTORC1 at that time improved killing of AML cells. |
| 2011 | A | Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice ANI2011 Female 129/Sv inbred mice received rapamycin intermittently, 2 weeks in every month, from 2 months of age for the rest of their lives. Treated mice gained less weight with age, showed a slower estimated rate of ageing, lived longer, with the gain most visible among the last survivors, and developed spontaneous tumours later. 22.9% of rapamycin-treated mice were still alive when the last control mouse died. The paper provided evidence that an intermittent rapamycin schedule can extend lifespan in a normal inbred mouse strain, adding to earlier results in genetically heterogeneous mice. Boundary: Female mice of a single inbred strain (129/Sv) only; drafted from the abstract only, so dose, group sizes and median-lifespan statistics are not given here. |
| 2001 | A | Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR NES2001 Tested whether tumour cells that have lost PTEN depend more on mTOR. The rapamycin analogue CCI-779 (temsirolimus) blocked growth of PTEN-null cells and tumours preferentially, and reversed the extra tumour growth caused by constitutively active Akt, placing mTOR downstream of Akt in tumour formation. PTEN loss went with higher S6 kinase activity and S6 phosphorylation. Sensitivity was not explained by how well the drug blocked S6 phosphorylation, since S6 was inhibited in sensitive and resistant lines alike. Boundary: worked from the abstract only (scanned PMC record); mouse and human cell lines and mouse tumour models, not patients. |
| 2001 | A | An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice POD2001 Transformed cells in Pten+/- mice showed raised phosphorylated Akt and active p70 S6 kinase together with faster proliferation. Treating the mice with an mTOR inhibitor reduced neoplastic proliferation, tumour size and S6 kinase activity without changing Akt status. The authors concluded that S6K and possibly other mTOR targets contribute to tumour development downstream of PTEN loss. Boundary: worked from the abstract only (scanned PMC record); mouse model. The abstract does not name the inhibitor. |
| 2026 | M | Firefox, a protein encoded by circular PVT1, is essential for MYC-driven oncogenesis. TIW2026 A micropeptide (Firefox/FFX) encoded by the circular RNA circPVT1 stimulates AKT-mTORC1 signaling and cap-dependent translation to sustain MYC protein abundance and transcriptional output. FFX depletion reduces MYC levels and impairs tumor growth in MYC-amplified xenograft models, identifying an mTORC1-linked vulnerability in MYC-driven cancers. |
| 2021 | M | mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis VIL2021 SAMTOR (GU2017) showed the cell can sense S-adenosylmethionine and report it to mTORC1. This study runs the arrow the other way: mTORC1 controls how much SAM the cell makes. Downstream of mTORC1, c-MYC binds intron 1 of MAT2A and raises expression of the enzyme that produces SAM, the cell's main methyl donor; mTORC1 separately increases the protein level of WTAP, the regulatory subunit of the m6A RNA methyltransferase complex. Together these raise m6A methylation of mRNA, which primes the translation machinery for growth. Blocking MAT2A lowers SAM, m6A, protein synthesis rate and tumor growth. |
| 2017 | M | mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability VAL2017 Hyperactive mTORC1 couples nucleotide synthesis to demand; imbalance drives replication stress in these cells. |
| 2012 | M | The translational landscape of mTOR signalling steers cancer initiation and metastasis HSI2012 Showed WHY mTOR-driven translation matters for cancer: in prostate cancer, oncogenic mTOR selectively translates a specific set of pro-invasion mRNAs that drive metastasis. An ATP-competitive mTOR inhibitor (INK128) reversed that signature - an early preclinical rationale from mouse models and cell lines, not a clinical result. |
| 2010 | M | Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E HSI2010 Genetic dissection shows the 4E-BP1-eIF4E axis mediates oncogenic mTOR signalling and is druggable. |
| 2008 | M | Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling DEY2008 Explains how low oxygen turns mTORC1 off. Growth factors keep TSC2 bound to inhibitory 14-3-3 proteins; under hypoxia REDD1 releases TSC2 from 14-3-3, which frees TSC2 to inhibit mTORC1. REDD1-null cells failed to release TSC2 or to switch mTORC1 off in hypoxia, and REDD1 mutants that cannot bind 14-3-3, or TSC2 mutants that cannot bind it, broke the signal. REDD1-null cells grew into far larger tumours in mice, and REDD1 was low in a subset of human breast carcinomas (8 of 27). Boundary: cell lines and mouse xenografts under acute hypoxia (hours); the human data are expression correlations only. |
| 2006 | M | TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth INO2006 TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation. |
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