MTOR

Overview

MTOR (Mechanistic Target of Rapamycin Kinase) is a serine/threonine kinase and central regulator of cell growth, metabolism, and survival through the PI3K/AKT/mTOR pathway. In clear cell renal cell carcinoma (ccRCC), activating MTOR mutations are strongly associated with resistance to both immunotherapy (ICI) and TKI-based regimens, marking it as a key biomarker of non-response in this disease.

Alterations observed in the corpus

  • Activating MTOR mutations strongly associated with ICI and ICI+TKI non-response in ccRCC (15/16 patients with MTOR mutations were resistant); enriched in the ICI-low score group by TCGA KIRC molecular subtyping PMID:22138691
  • MTOR pathway activation is a recurrent feature of hepatocellular carcinoma (HCC) genomics; reviewed as a potential therapeutic target PMID:22634756
  • Among the top eight most significantly mutated genes (q<0.00001) in ccRCC; mutation enriched in m4 mRNA subtype (12% vs 4%, p=0.01); nominated as a therapeutic target, supporting use of everolimus and temsirolimus in advanced RCC PMID:23792563
  • Pathway downstream of PI3K/AKT in the PI3K/AKT/mTOR signaling map; combined PI3K/AKT/mTOR pathway altered in 30% of high-grade urothelial bladder tumors; TSC1-null tumors resistant to AKT inhibition (MK-2206) while maintaining S6/4EBP1 signaling PMID:23897969
  • TMZ-associated activating mutation S2215F validated as constitutively activating in low-grade glioma; subclonal expansion of MTOR-mutant cells drove distal recurrence in patient 01 of the longitudinal cohort PMID:24336570
  • MTOR is listed among manually reviewed ccRCC driver genes; the PI3K–mTOR pathway shows mutation prevalence reaching 60% per case across multi-region sequencing, with single-biopsy designs substantially underestimating this prevalence PMID:24487277
  • Somatic mutation in 2/66 chromophobe RCC cases; combined mTOR-pathway alteration rate (PTEN, MTOR, TSC1/2, NRAS) of 23% in ChRCC suggests candidates for mTOR-directed therapy PMID:25155756
  • Recurrent mutations in chRCC alongside TSC1/TSC2, suggesting mTORC1 addiction; identified among 60 genes with COSMIC hotspot mutations as potential drug targets in nccRCC; mTORC1 inhibitors (rapalogs) nominated as candidate therapy PMID:25401301
  • MTOR S2215F (validated activating allele) identified in metastatic cSCC (n=29); RAS/RTK/PI3K pathway activation including MTOR events correlated with shorter PFS (mean 12 vs 50 months), motivating mTOR inhibitor evaluation. PMID:25589618
  • In hepatocellular carcinoma (HCC), MTOR mutations occur in 2% of cases and are FDA-targetable; MTOR is a component of the PI3K/AKT/mTOR pathway altered in 51% of HCC. PMID:25822088
  • Non-passenger mutation in PI3K/mTOR pathway in breast adenoid cystic carcinoma (AdCC); subclonal in at least one case PMID:26095796
  • mTORC1 pathway (p-mTOR, p-4E-BP1 T37/46, p-S6 S235/236) activated in SF3B1-mutant/del(13q) CLL cells; targetable with temsirolimus; mTORC1 activation driven by SF3B1-K700E-induced NFATC1 isoform 5 PMID:26200345
  • Rare activating mutations contributing to PI3K-pathway aberration in prostate adenocarcinoma in the TCGA cohort (n=333) PMID:26544944
  • MTOR is part of the PI3K/AKT/mTOR pathway disrupted in 39% of ATC vs 11% of PDTC (P = 1×10⁻³); pathway disruption includes PIK3CA, PTEN, AKT3, TSC1, TSC2, and MTOR alterations; supports use of mTOR inhibitors in ATC PMID:26878173
  • PI3K/mTOR pathway event in cisplatin-resistant GCT; mTOR inhibitors listed as targeted therapy candidates for PI3K-pathway alterations in cisplatin-resistant patients PMID:27646943
  • Missense mutations in 8% of unclassified RCC (uRCC); recurrent L2427R (×3) is functionally activating; co-occurs with TSC1/TSC2/PTEN alterations defining a mutually exclusive mTORC1-hyperactive uRCC subset responsive to mTOR inhibitors PMID:27713405
  • 1 patient with S2215Y as highest driver; 1 UMD patient with novel L2383F missense had 1-month no-benefit course on everolimus in prospective LUAD cohort (860 patients, MSK-IMPACT) PMID:28336552
  • MTOR was identified as a functional oncogene in DLBCL by CRISPR screen (its knockout depleted cell growth across lines) and was a driver gene in 1001 DLBCL patients; MTOR mutations are prevalent in DLBCL but associate with generally good outcomes in the GCB subtype, suggesting patients with MTOR alterations may be underrepresented in clinical trials of MTOR inhibitors PMID:28985567
  • Aberrant PI3K-AKT-MTOR signaling is recurrent in leiomyosarcoma (LMS), with frequent amplification and upregulation of MTOR along with PTEN deletion/mutation, IGF1R, AKT, and RICTOR alterations; MTOR inhibitors (everolimus, temsirolimus) have shown limited clinical efficacy in LMS; dual PI3K/MTOR inhibitors may offer improved outcomes PMID:29100075
  • Called as a significantly mutated gene (SMG) in KIRC by both MutSig2CV and MuSiC2 on the TCGA MC3 open-access MAF; confirmed as a consensus driver in clear cell renal cell carcinoma across two independent callers. PMID:29596782

Cancer types (linked)

  • KIRC: Activating mutations present in a subset of ccRCC tumors and strongly predict non-response to immunotherapy and TKI combinations; MTOR-mutant patients may represent a distinct therapeutic category PMID:22138691

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • MTOR-mutant ccRCC is classified as non-responsive (3% of patients) by the integrated decision-tree model, suggesting these patients may require alternative strategies beyond standard ICI or TKI regimens; mTOR inhibitors (everolimus, temsirolimus) are approved in ccRCC but were not specifically evaluated for this mutation-defined subgroup in the corpus PMID:22138691

Open questions

  • Whether MTOR-mutant ccRCC patients benefit from mTOR-targeted agents (everolimus, temsirolimus) over ICI or TKI combinations is not resolved in the corpus.
  • The specific MTOR mutation spectrum (hotspot vs. scattered) in the non-responsive group has not been detailed.

Sources

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