RICTOR

Gene Summary

Gene:RICTOR; RPTOR independent companion of MTOR complex 2
Aliases: PIA, AVO3, hAVO3
Location:5p13.1
Summary:RICTOR and MTOR (FRAP1; MIM 601231) are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth (Sarbassov et al., 2004 [PubMed 15268862]).[supplied by OMIM, Mar 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:rapamycin-insensitive companion of mTOR
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Carrier Proteins
  • Proteins
  • Phosphatidylinositol 3-Kinases
  • Ribosomal Protein S6 Kinases
  • ras Proteins
  • Cell Proliferation
  • Messenger RNA
  • Chromosome 5
  • Epidermal Growth Factor Receptor
  • Multiprotein Complexes
  • RTPCR
  • Cell Survival
  • MicroRNAs
  • VEGFA
  • rac1 GTP-Binding Protein
  • Immunohistochemistry
  • siRNA
  • Wound Healing
  • Western Blotting
  • AKT1
  • Sirolimus
  • Gene Expression Profiling
  • Phosphorylation
  • Up-Regulation
  • Cancer Gene Expression Regulation
  • Ubiquitination
  • Neoplasm Invasiveness
  • Transcription Factors
  • Signal Transducing Adaptor Proteins
  • Cell Movement
  • Neoplastic Cell Transformation
  • Prostate Cancer
  • Breast Cancer
  • RNA Interference
  • Protein Binding
  • VHL
  • Signal Transduction
  • Transforming Growth Factor beta
  • Apoptosis
  • Mutation
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RICTOR (cancer-related)

Zhou L, Liu S, Han M, et al.
MicroRNA-185 induces potent autophagy via AKT signaling in hepatocellular carcinoma.
Tumour Biol. 2017; 39(2):1010428317694313 [PubMed] Related Publications
Studies have demonstrated that microRNA 185 may be a promising therapeutic target in liver cancer. However, its role in hepatocellular carcinoma is largely unknown. In this study, the proliferation of human HepG2 cells was inhibited by transfection of microRNA 185 mimics. Cell-cycle analysis revealed arrest at the G0/G1 phase. Transfection of HepG2 cells with microRNA 185 mimics significantly induced apoptosis. These data confirmed microRNA 185 as a potent cancer suppressor. We demonstrated that microRNA 185 was a compelling inducer of autophagy, for the first time. When cell autophagy was inhibited by chloroquine or 3-methyladenine, microRNA 185 induced more cell apoptosis. MicroRNA 185 acted as a cancer suppressor by regulating AKT1 expression and phosphorylation. Dual-luciferase reporter assays indicated that microRNA 185 suppressed the expression of target genes including RHEB, RICTOR, and AKT1 by directly interacting with their 3'-untranslated regions. Binding site mutations eliminated microRNA 185 responsiveness. Our findings demonstrate a new role of microRNA 185 as a key regulator of hepatocellular carcinoma via autophagy by dysregulation of AKT1 pathway.

Vandamme T, Beyens M, de Beeck KO, et al.
Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors.
Br J Cancer. 2016; 114(6):650-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described.
METHODS: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose-response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT-qPCR).
RESULTS: Long-term everolimus-treated BON-1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10-12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed.
CONCLUSIONS: Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1.

Micevic G, Muthusamy V, Damsky W, et al.
DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR.
Cell Rep. 2016; 14(9):2180-92 [PubMed] Free Access to Full Article Related Publications
DNA methyltransferase DNMT3B is frequently overexpressed in tumor cells and plays important roles during the formation and progression of several cancer types. However, the specific signaling pathways controlled by DNMT3B in cancers, including melanoma, are poorly understood. Here, we report that DNMT3B plays a pro-tumorigenic role in human melanoma and that DNMT3B loss dramatically suppresses melanoma formation in the Braf/Pten mouse melanoma model. Loss of DNMT3B results in hypomethylation of the miR-196b promoter and increased miR-196b expression, which directly targets the mTORC2 component Rictor. Loss of RICTOR in turn prevents mTORC2 activation, which is critical for melanoma formation and growth. These findings establish Dnmt3b as a regulator of melanoma formation through its effect on mTORC2 signaling. Based on these results, DNMT3B is a potential therapeutic target in melanoma.

Packer JR, Maitland NJ
The molecular and cellular origin of human prostate cancer.
Biochim Biophys Acta. 2016; 1863(6 Pt A):1238-60 [PubMed] Related Publications
Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency. Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background "field" for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression. In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells. Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR-neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs.

Dowlati A, Lipka MB, McColl K, et al.
Clinical correlation of extensive-stage small-cell lung cancer genomics.
Ann Oncol. 2016; 27(4):642-7 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Genomic studies in small-cell lung cancer (SCLC) lag far behind those carried out in nonsmall-cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of 'every-day' SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.
PATIENTS AND METHODS: A total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan-Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or immunohistochemistry of tumor specimens.
RESULTS: In all, 39 patients had ES-SCLC; 15 patients had either primary refractory/resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low-frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (P = 0.038) in predicting response to first-line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 with wild-type. Patients with mutant RB1 had both better OS (11.7 versus 9.1 months P = 0.04) and PFS (11.2 versus 8.6 months, P = 0.06) compared with patients with wild-type RB1. Interestingly, ∼25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.
CONCLUSIONS: We found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.

Ali SM, Pal SK, Wang K, et al.
Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations.
Oncologist. 2016; 21(1):33-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs).
MATERIALS AND METHODS: DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 692× for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials.
RESULTS: Twenty male patients with a median age of 60 years (range, 46-87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (2.2 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), PIK3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), RICTOR amplifications (10%), and FBXW7 point mutations (10%).
CONCLUSION: CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and PIK3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients.
IMPLICATIONS FOR PRACTICE: Few treatment options exist for patients with advanced penile squamous cell carcinoma (PSCC). Outcomes are dismal with platinum-based chemotherapy, with median survival estimated at 1 year or less across multiple series. Biological studies of patients with PSCC to date have principally focused on human papillomavirus status, but few studies have elucidated molecular drivers of the disease. To this end, comprehensive genomic profiling was performed in a cohort of 20 patients with advanced PSCC. Findings of frequent mutations in CDKN2A, NOTCH1, PIK3CA, and EGFR (all in excess of 20%) point to potential therapeutic avenues. Trials of targeted therapies directed toward these mutations should be explored.

Vieira GC, Chockalingam S, Melegh Z, et al.
LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma.
Oncotarget. 2015; 6(37):40053-67 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
LGR5 is a marker of normal and cancer stem cells in various tissues where it functions as a receptor for R-spondins and increases canonical Wnt signalling amplitude. Here we report that LGR5 is also highly expressed in a subset of high grade neuroblastomas. Neuroblastoma is a clinically heterogenous paediatric cancer comprising a high proportion of poor prognosis cases (~40%) which are frequently lethal. Unlike many cancers, Wnt pathway mutations are not apparent in neuroblastoma, although previous microarray analyses have implicated deregulated Wnt signalling in high-risk neuroblastoma. We demonstrate that LGR5 facilitates high Wnt signalling in neuroblastoma cell lines treated with Wnt3a and R-spondins, with SK-N-BE(2)-C, SK-N-NAS and SH-SY5Y cell-lines all displaying strong Wnt induction. These lines represent MYCN-amplified, NRAS and ALK mutant neuroblastoma subtypes respectively. Wnt3a/R-Spondin treatment also promoted nuclear translocation of β-catenin, increased proliferation and activation of Wnt target genes. Strikingly, short-interfering RNA mediated knockdown of LGR5 induces dramatic Wnt-independent apoptosis in all three cell-lines, accompanied by greatly diminished phosphorylation of mitogen/extracellular signal-regulated kinases (MEK1/2) and extracellular signal-regulated kinases (ERK1/2), and an increase of BimEL, an apoptosis facilitator downstream of ERK. Akt signalling is also decreased by a Rictor dependent, PDK1-independent mechanism. LGR5 expression is cell cycle regulated and LGR5 depletion triggers G1 cell-cycle arrest, increased p27 and decreased phosphorylated retinoblastoma protein. Our study therefore characterises new cancer-associated pathways regulated by LGR5, and suggest that targeting of LGR5 may be of therapeutic benefit for neuroblastomas with diverse etiologies, as well as other cancers expressing high LGR5.

Sun B, Chen L, Fu H, et al.
Upregulation of RICTOR gene transcription by the proinflammatory cytokines through NF-κB pathway contributes to the metastasis of renal cell carcinoma.
Tumour Biol. 2016; 37(4):4457-66 [PubMed] Related Publications
Metastasis accounts for more than 50 % of deaths among renal cell carcinoma (RCC) patients, and therefore, it is important to study the biology of metastasis and identify metastasis-associated biomarkers for risk prognosis and stratification of patients for an individualized therapy of RCC. In cultured RCC cells, knockdown of Rictor by short hairpin RNA (shRNA) inhibited cell migration and invasion, probably due to impairments in activation of Akt. Pretreatment with tumor necrosis factor α (TNFα) or interleukin 6 (IL-6) enhanced the expression of Rictor and the migration of renal cancer cells. Mechanistic analysis showed that TNFα induced the activation of NF-κB in RCC cells. Luciferase reporter analysis revealed a NF-κB responding element (-301 to -51 bp) at the promoter region of Rictor. Chromatin immunoprecipitation (ChIP) analysis further confirmed that TNFα-induced binding of p65 with the promoter of Rictor. In a xenograft model, knockdown of Rictor-blocked RCC cells metastasis to the mouse lungs and livers. Taken together, our results suggest that the proinflammatory cytokine TNFα promotes the expression of Rictor through the NF-κB pathway.

Li L, Pilo GM, Li X, et al.
Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans.
J Hepatol. 2016; 64(2):333-41 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND & AIMS: Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver.
METHODS: FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA.
RESULTS: Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with a strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice.
CONCLUSIONS: FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.

Feng X, Tian L, Zhang Z, et al.
Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis.
Oncotarget. 2015; 6(32):32353-67 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cytotoxic radiotherapy unfavorably induces tumor cells to generate various proangiogenic substances, promoting post-irradiation angiogenesis (PIA), which is one of major causes of radiotherapy failure. Though several studies have reported some mechanisms behind PIA, they have not yet described the beginning proangiogenic motivator buried in the irradiated microenvironment. In this work, we revealed that dying tumor cells induced by irradiation prompted PIA via a caspase 3 dependent mechanism. Proteolytic inactivation of caspase 3 in dying tumor cells by transducing a dominant-negative version weakened proangiogenic effects in vitro and in vivo. In addition, inhibition of caspase 3 activity suppressed tumor angiogenesis and tumorigenesis in xenograft mouse model. Importantly, we identified vascular endothelial growth factor (VEGF)-A as a downstream proangiogenic factor regulated by caspase 3 possibly through Akt signaling. Collectively, these findings indicated that besides acting as a key executioner in apoptosis, caspase 3 in dying tumor cells may play a central role in driving proangiogenic response after irradiation. Thus, radiotherapy in combination with caspase 3 inhibitors may be a novel promising therapeutic strategy to reduce tumor recurrence due to restrained PIA.

Cheng H, Zou Y, Ross JS, et al.
RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors.
Cancer Discov. 2015; 5(12):1262-70 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: We identified amplification of RICTOR, a key component of the mTOR complex 2 (mTORC2), as the sole actionable genomic alteration in an 18-year-old never-smoker with lung adenocarcinoma. Amplification of RICTOR occurs in 13% of lung cancers (1,016 cases) in The Cancer Genome Atlas and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTORC1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared with other agents targeting the PI3K-AKT-mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTORC1/2 inhibitors was observed. The index patient has been treated with mTORC1/2 inhibitors that led to tumor stabilization for more than 18 months.
SIGNIFICANCE: RICTOR amplification may define a novel and unique molecular subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors.

Shuhua W, Chenbo S, Yangyang L, et al.
Autophagy-related genes Raptor, Rictor, and Beclin1 expression and relationship with multidrug resistance in colorectal carcinoma.
Hum Pathol. 2015; 46(11):1752-9 [PubMed] Related Publications
UNLABELLED: This study aims to evaluate the relationship between the expressions of autophagy-related genes Raptor, Rictor, and Beclin1 and the expression of multidrug resistance (MDR) gene in colorectal cancer (CRC) patients. Immunohistochemistry and real-time polymerase chain reaction were used to detect the protein and messenger RNA expressions of mammalian target of rapamycin (mTOR), Raptor, Rictor, Beclin1, light chain 3 (LC3), and MDR-1 in 279 CRC specimens. Patients were followed up annually by telephone or at an outpatient clinic. Results revealed that the protein and messenger RNA expressions of Beclin1, LC3, mTOR, Raptor, Rictor, and MDR-1 in CRC are significantly higher than in adjacent tissues. LC3 expression in poorly differentiated CRC is higher than that in well-differentiated CRC, and the expression of mTOR, Raptor, Rictor, and LC3 in lymph node metastasis is higher than that obtained in the absence of lymph node metastasis. The expression of LC3 is positively correlated with those of Beclin1 and Rictor and negatively correlated with Raptor and mTOR in CRC. The expression of Raptor is negatively correlated with Rictor. The expression of MDR-1 is positively correlated with those of Beclin1, LC3, and Rictor and negatively correlated with Raptor and mTOR. Kaplan-Meier analysis revealed that the 5-year survival rate of patients without lymph node metastasis; positive expression of Rictor, Beclin1, and LC3; and negative expression of Raptor and mTOR were higher than those with these characteristics. To conclude, the expressions of Beclin1, Raptor, and Rictor are related to the development and progression of colorectal carcinoma and MDR. (
CLINICAL TRIAL REGISTRATION NUMBER: 2014-009-01.).

Park J, Lee J, Choi C
Evaluation of drug-targetable genes by defining modes of abnormality in gene expression.
Sci Rep. 2015; 5:13576 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
In the post-genomic era, many researchers have taken a systematic approach to identifying abnormal genes associated with various diseases. However, the gold standard has not been established, and most of these abnormalities are difficult to be rehabilitated in real clinical settings. In addition to identifying abnormal genes, for a practical purpose, it is necessary to investigate abnormality diversity. In this context, this study is aimed to demonstrate simply restorable genes as useful drug targets. We devised the concept of "drug targetability" to evaluate several different modes of abnormal genes by predicting events after drug treatment. As a representative example, we applied our method to breast cancer. Computationally, PTPRF, PRKAR2B, MAP4K3, and RICTOR were calculated as highly drug-targetable genes for breast cancer. After knockdown of these top-ranked genes (i.e., high drug targetability) using siRNA, our predictions were validated by cell death and migration assays. Moreover, inhibition of RICTOR or PTPRF was expected to prolong lifespan of breast cancer patients according to patient information annotated in microarray data. We anticipate that our method can be widely applied to elaborate selection of novel drug targets, and, ultimately, to improve the efficacy of disease treatment.

Morandi L, Gissi D, Tarsitano A, et al.
DNA methylation analysis by bisulfite next-generation sequencing for early detection of oral squamous cell carcinoma and high-grade squamous intraepithelial lesion from oral brushing.
J Craniomaxillofac Surg. 2015; 43(8):1494-500 [PubMed] Related Publications
PURPOSE: Oral squamous cell carcinoma (OSCC) is commonly preceded by oral potentially malignant lesions (OPML). The aim of the present study was to assess, by bisulfite next-generation sequencing (NGS), the methylation status of a list of candidate genes obtained from oral brushings to early detect OPML and OSCC.
MATERIAL AND METHODS: Oral brushing specimens from 11 OSCC, 11 high-grade squamous intraepithelial lesions (HG-SIL), 9 low-grade SIL (LG-SIL), 9 oral lichen planus (OLP), and 8 healthy donors were included in this study. We investigated, by means of bisulfite NGS, the promoter of GP1BB, ZAP70, KIF1A, p16[CDKN2A], CDH1, miR137, and miR375. Statistical significance between lesions and a pool of healthy donors were evaluated with the Mann-Whitney U test.
RESULTS: ZAP70 was found to be hypermethylated in 100% of OSCC and HG-SIL and in 28.6% of LG-SIL. GP1BB hypomethylation was detected in 90.9% OSCC and HG-SIL and in 37.5% of LG-SIL. MiR137 was hypermethylated in 100% of OLP, 44.4% of OSCC, 40% HG-SIL, and 25% LG-SIL. KIF1A hypermethylation was found to be associated with TP53 mutations (p < 0.0001).
CONCLUSION: In the present preliminary cohort of patients, DNA methylation analysis of GP1BB and ZAP70 seems to be a promising noninvasive tool for early detection of OSCC and HG SIL from oral brushing specimens.

Kunoh T, Wang W, Kobayashi H, et al.
Human Dynactin-Associated Protein Transforms NIH3T3 Cells to Generate Highly Vascularized Tumors with Weak Cell-Cell Interaction.
PLoS One. 2015; 10(8):e0135836 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Human dynactin-associated protein (dynAP) is a transmembrane protein that promotes AktSer473 phosphorylation. Here, we report the oncogenic properties of dynAP. In contrast to control NIH3T3 cells expressing LacZ (NIH3T3LacZ), NIH3T3dynAP cells vigorously formed foci in two-dimensional culture, colonies on soft agar, and spheroids in anchorage-deficient three-dimensional culture. NIH3T3dynAP cells injected into nude mice produced tumors with abundant blood vessels and weak cell-cell contacts. Expression of dynAP elevated the level of rictor (an essential subunit of mTORC2) and promoted phosphorylation of FOXO3aSer253. FOXO3a is a transcriptional factor that stimulates expression of pro-apoptotic genes and phosphorylation of FOXO3a abrogates its function, resulting in promoted cell survival. Knockdown of rictor in NIH3T3dynAP cells reduced AktSer473 phosphorylation and formation of foci, colony in soft agar and spheroid, indicating that dynAP-induced activation of the mTORC2/AktSer473 pathway for cell survival contributes to cell transformation. E-cadherin and its mRNA were markedly reduced upon expression of dynAP, giving rise to cells with higher motility, which may be responsible for the weak cell-cell adhesion in tumors. Thus, dynAP could be a new oncoprotein and a target for cancer therapy.

Ross JS, Wang K, Gay L, et al.
Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies.
JAMA Oncol. 2015; 1(1):40-9 [PubMed] Related Publications
IMPORTANCE: For carcinoma of unknown primary site (CUP), determining the primary tumor site may be uninformative and often does not improve outcome.
OBJECTIVE: To discover opportunities for targeted therapies in patients with CUP not currently searched for in routine practice.
DESIGN, SETTING, AND PARTICIPANTS: Comprehensive genomic profiling on 200 CUP formalin-fixed paraffin-embedded specimens (mean, 756× coverage) using the hybrid-capture-based FoundationOne assay at academic and community oncology clinics.
MAIN OUTCOMES AND MEASURES: Presence of targetable genomic alterations (GAs) in CUP and responses to targeted therapies.
RESULTS: There were 125 adenocarcinomas of unknown primary site (ACUPs) and 75 carcinomas of unknown primary site without features of adenocarcinoma (non-ACUPs). At least 1 GA was found in 192 (96%) of CUP specimens, with a mean (SD) of 4.2 (2.8) GAs per tumor. The most frequent GAs were in TP53 (110 [55%]), KRAS (40 [20%]), CDKN2A (37 [19%]), MYC (23 [12%]), ARID1A (21 [11%]), MCL1 (19 [10%]), PIK3CA (17 [9%]), ERBB2 (16 [8%]), PTEN (14 [7%]), EGFR (12 [6%]), SMAD4 (13 [7%]), STK11 (13 [7%]), SMARCA4 (12 [6%]), RB1 (12 [6%]), RICTOR (12 [6%]), MLL2 (12 [6%]), BRAF (11 [6%]), and BRCA2 (11 [6%]). One or more potentially targetable GAs were identified in 169 of 200 (85%) CUP specimens. Mutations or amplifications of ERBB2 were more frequent in ACUPs (13 [10%]) than in non-ACUPs (3 [4%]). Alterations of EGFR (10 [8%] vs 2 [3%]) and BRAF (8 [6%] vs 3 [4%]) were more common in ACUPs than in non-ACUPs. Strikingly, clinically relevant alterations in the receptor tyrosine kinase (RTK)/Ras signaling pathway including alterations in ALK, ARAF, BRAF, EGFR, FGFR1, FGFR2, KIT, KRAS, MAP2K1, MET, NF1, NF2, NRAS, RAF1, RET, and ROS1 were found in 90 (72%) ACUPs but in only 29 (39%) non-ACUPs (P < .001).
CONCLUSIONS AND RELEVANCE: Almost all CUP samples harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. The ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway than the non-ACUP tumors. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with CUP.

Jiang S, Zou Z, Nie P, et al.
Synergistic Effects between mTOR Complex 1/2 and Glycolysis Inhibitors in Non-Small-Cell Lung Carcinoma Cells.
PLoS One. 2015; 10(7):e0132880 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR) is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1), drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC) A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.

Masui K, Tanaka K, Ikegami S, et al.
Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance.
Proc Natl Acad Sci U S A. 2015; 112(30):9406-11 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.

Bian Y, Wang Z, Xu J, et al.
Elevated Rictor expression is associated with tumor progression and poor prognosis in patients with gastric cancer.
Biochem Biophys Res Commun. 2015; 464(2):534-40 [PubMed] Related Publications
The rapamycin insensitive companion of mTOR (Rictor) is an essential subunit of mTOR complex 2 (mTORC2), maintains the integrity of the complex and functions as regulator of Akt full activation. Rictor has been implicated to be involved in growth and progression of malignancies, however, little is known about its expression and prognostic role in gastric cancer in particular. Therefore, we investigated the relationship of Rictor expression with clinical outcomes, together with pAktSer473 and pS6, two downstream substrates of mTORC2 and mTORC1, in 396 gastric cancer tissue samples via immunohistochemistry. The results showed that 74.0% and 55.8% of tumors were Rictor and pAktSer473 positive staining, respectively, which correlated well with each other. Patients with positive expressions had poorer overall survival and relapse-free survival compared with those negative staining. Both Rictor and pAktSer473 expression were associated with lymph node metastasis, TNM stage, and WHO grading. Rictor was also correlated with tumor size, depth of invasion, and tumor thrombus, while pAktSer473 was also correlated with distant metastasis. In spite of 67.4% expression rate was presented in gastric cancer tissues, no significant association was observed between pS6Ser235/236, representing mTORC1 activity, and clinicopathological features or prognosis. These results suggest that mTORC2/Rictor/pAkt may play a more important role than mTORC1/pS6 in tumor progression, which could act as a prognostic biomarker or potential therapeutic target in gastric cancer.

Artinian N, Cloninger C, Holmes B, et al.
Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness.
J Biol Chem. 2015; 290(32):19387-401 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The mechanistic target of rapamycin (mTOR) and Hippo signaling pathways are two major signaling cascades that coordinately regulate cell growth and proliferation. Dysregulation of these pathways plays a critical role in gliomagenesis. Recent reports have provided evidence of cross-talk between the mTOR and Hippo pathways; however, a complete description of the signaling relationships between these pathways remains to be elucidated. Utilizing a gene-trapping strategy in a mouse glioma model, we report the identification of AMOTL2 as a candidate substrate for mTORC2. AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets. Moreover, overexpression of AMOTL2 or a nonphosphorylatable AMOTL2-S760A mutant inhibited YAP-induced transcription, foci formation, growth, and metastatic properties, whereas overexpression of a phosphomimetic AMOTL2-S760E mutant negated these repressive effects of AMOTL2 in glioblastoma (GBM) cells in vitro. Similar effects on xenograft growth were observed in GBM cells expressing these AMOTL2 Ser(760) mutants. YAP was also shown to be required for Rictor-mediated GBM growth and survival. Finally, an analysis of mTORC2/AMOTL2/YAP activities in primary GBM samples supported the clinical relevance of this signaling cascade, and we propose that pharmacological agents cotargeting these regulatory circuits may hold therapeutic potential.

Parish A, Schwaederle M, Daniels G, et al.
Fibroblast growth factor family aberrations in cancers: clinical and molecular characteristics.
Cell Cycle. 2015; 14(13):2121-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Fibroblast growth factor ligands and receptors (FGF and FGFR) play critical roles in tumorigenesis, and several drugs have been developed to target them. We report the biologic correlates of FGF/FGFR abnormalities in diverse malignancies. The medical records of patients with cancers that underwent targeted next generation sequencing (182 or 236 cancer-related genes) were reviewed. The following FGF/FGFR genes were tested: FGF3, 4, 6, 7, 10, 12, 14, 19, 23 and FGFR1, 2, 3, and 4. Of 391 patients, 56 (14.3%) had aberrant FGF (N = 38, all amplifications) and/or FGFR (N = 22 including 5 mutations and one FGFR3-TACC3 fusion). FGF/FGFR aberrations were most frequent in breast cancers (26/81, 32.1%, p = 0.0003). In multivariate analysis, FGF/FGFR abnormalities were independently associated with CCND1/2, RICTOR, ZNF703, RPTOR, AKT2, and CDK8 alterations (all P < 0.02), as well as with an increased median number of alterations (P < 0.0001). FGF3, FGF4, FGF19 and CCND1 were co-amplified in 22 of 391 patients (5.6%, P < 0.0001), most likely because they co-localize on the same chromosomal region (11q13). There was no significant difference in time to metastasis or overall survival when comparing patients harboring FGF/FGFR alterations versus those not. Overall, FGF/FGFR was one of the most frequently aberrant pathways in our population comprising patients with diverse malignancies. These aberrations frequently co-exist with anomalies in a variety of other genes, suggesting that tailored combination therapy may be necessary in these patients.

Chen HH, Huang WT, Yang LW, Lin CW
The PTEN-AKT-mTOR/RICTOR Pathway in Nasal Natural Killer Cell Lymphoma Is Activated by miR-494-3p via PTEN But Inhibited by miR-142-3p via RICTOR.
Am J Pathol. 2015; 185(5):1487-99 [PubMed] Related Publications
Nasal natural killer (NK) cell lymphoma (NNL) is an Epstein-Barr virus-associated lymphoma of cytotoxic NK cell origin. The Epstein-Barr virus-encoded miR-BART20-5p inhibits T-bet (TBX21), the master transcription factor of cytotoxic NK cells. To further explore the roles of miRNAs in NNLs, we measured the miRNA expression profiles of 36 NNLs. miR-21, miR-142-3p, miR-126, miR-451, and miR-494-3p were the top five miRNAs with the highest expression levels. By using pathway analysis, we identified associations between all of the five miRNAs with the PTEN-AKT-mTOR pathway, in which PTEN suppresses the oncogenic AKT, and mTOR mediates the oncogenic effects of AKT. YT and NK92 cells derived from NK cell lymphomas were used. miR-494-3p inhibited PTEN with secondary activation of AKT in NK92 cells, and miR-142-3p inhibited RICTOR, a key component of the mTOR complex, with secondary suppression of AKT in YT cells. Significantly, T-bet inhibited the PTEN-AKT-mTOR/RICTOR pathway through induction of PTEN and suppression of RICTOR. Therefore, a molecular circuit of T-bet, PTEN, AKT, and RICTOR is regulated by miR-BART20-5p, miR-494-3p, and miR-142-3p. This circuit is involved in the pathogenesis of NNL. Hence, antagomirs to miR-BART20-5p or miR-494-3p, miR-142-3p mimics, or AKT inhibitors may be useful in NNL therapy.

Chatterjee P, Seal S, Mukherjee S, et al.
A carbazole alkaloid deactivates mTOR through the suppression of rictor and that induces apoptosis in lung cancer cells.
Mol Cell Biochem. 2015; 405(1-2):149-58 [PubMed] Related Publications
Non-small cell lung cancer (NSCLC) is known to be a difficult cancer to treat because of its poor prognosis, limited option for surgery, and resistance to chemo or radiotherapy. In this study, we have demonstrated that suppression of rictor expression in A549 and H1299 NSCLC cells by mahanine, a carbazole alkaloid, disrupted constitutive activation of mTOR and Akt. Mahanine suppression of rictor gene expression and consequent attenuation of its protein expression affected the inhibition of mTOR (Ser-2481) and Akt (Ser-473) phosphorylation. Since mahanine treatment revealed this new insight of rictor-mTOR relationship, we examined an association between mTOR activation with rictor expression. Interestingly, in rictor knockdown (KD) NSCLC cells, mTOR activation was significantly impaired. Transfection of rictor over-expression vector into the NSCLC cells reversed this situation. In fact, both rictor KD and mahanine treated cells showed considerably depleted phospho-mTOR level. These results indicate that rictor is required to maintain constitutive activation of mTOR in lung cancer cells. When mTOR kinase activity in rictor KD cells was examined with Akt as substrate, a significant reduction of Akt phosphorylation indicated impairment of mTOR kinase potentiality. Disruption of mTOR and Akt activation caused drastic mortality of NSCLC cancer cells through apoptosis. Hence, our study reveals a new dimension in mTOR-rictor relationship, where rictor stands to be a suitable therapeutic target for lung cancer.

Li S, Oh YT, Yue P, et al.
Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells.
Oncogene. 2016; 35(5):642-50 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cancer cells feature increased de novo lipogenesis. Sterol regulatory element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), enhances lipogenesis by increasing transcription of several of its target genes. Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism. A role for mTORC1 in the regulation of SREBP1 activity has been suggested; however, the connection between mTORC2 and SREBP1 has not been clearly established and hence is the focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 compared with parent or rictor-deficient cells with re-expression of ectopic rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a novel biological function of mTORC2 in the regulation of lipogenesis and warrant further study in this direction.

Koelzer VH, Herrmann P, Zlobec I, et al.
Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 (MACC1) for survival prognosis of colorectal cancer patients: a retrospective cohort study.
BMC Cancer. 2015; 15:160 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Metastasis of colorectal cancer (CRC) is directly linked to patient survival. We previously identified the novel gene Metastasis Associated in Colon Cancer 1 (MACC1) in CRC and demonstrated its importance as metastasis inducer and prognostic biomarker. Here, we investigate the geographic expression pattern of MACC1 in colorectal adenocarcinoma and tumor buds in correlation with clinicopathological and molecular features for improvement of survival prognosis.
METHODS: We performed geographic MACC1 expression analysis in tumor center, invasive front and tumor buds on whole tissue sections of 187 well-characterized CRCs by immunohistochemistry. MACC1 expression in each geographic zone was analyzed with Mismatch repair (MMR)-status, BRAF/KRAS-mutations and CpG-island methylation.
RESULTS: MACC1 was significantly overexpressed in tumor tissue as compared to normal mucosa (p < 0.001). Within colorectal adenocarcinomas, a significant increase of MACC1 from tumor center to front (p = 0.0012) was detected. MACC1 was highly overexpressed in 55% tumor budding cells. Independent of geographic location, MACC1 predicted advanced pT and pN-stages, high grade tumor budding, venous and lymphatic invasion (p < 0.05). High MACC1 expression at the invasive front was decisive for prediction of metastasis (p = 0.0223) and poor survival (p = 0.0217). The geographic pattern of MACC1 did not correlate with MMR-status, BRAF/KRAS-mutations or CpG-island methylation.
CONCLUSION: MACC1 is differentially expressed in CRC. At the invasive front, MACC1 expression predicts best aggressive clinicopathological features, tumor budding, metastasis formation and poor survival outcome.

Chen L, Xu B, Liu L, et al.
Both mTORC1 and mTORC2 are involved in the regulation of cell adhesion.
Oncotarget. 2015; 6(9):7136-50 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
mTOR is a central controller for cell growth/proliferation and survival. Recent studies have shown that mTOR also regulates cell adhesion, yet the underlying mechanism is not known. Here we found that inhibition of mTOR by rapamycin reduced the basal or type I insulin-like growth factor (IGF-1)-stimulated adhesion of cancer cells. Further research revealed that both mTORC1 and mTORC2 were involved in the regulation of cell adhesion, as silencing expression of raptor or rictor inhibited cell adhesion. Also, PP242, an mTORC1/2 kinase inhibitor, inhibited cell adhesion more potently than rapamycin (mTORC1 inhibitor). Of interest, ectopic expression of constitutively active and rapamycin-resistant mutant of p70 kinase 1 (S6K1) or downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) conferred resistance to rapamycin inhibition of cell adhesion, whereas expression of constitutively hypophosphorylated 4E-BP1 (4EBP1-5A) or downregulation of S6K1 suppressed cell adhesion. In contrast, neither genetic manipulation of Akt activity nor pharmacological inhibition of Akt affected cell adhesion. The results suggest that both mTORC1 and mTORC2 are involved in the regulation of cell adhesion; and mTORC1 regulates cell adhesion through S6K1 and 4E-BP1 pathways, but mTORC2 regulates cell adhesion via Akt-independent mechanism.

Zheng G, Jia X, Peng C, et al.
The miR-491-3p/mTORC2/FOXO1 regulatory loop modulates chemo-sensitivity in human tongue cancer.
Oncotarget. 2015; 6(9):6931-43 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We found that levels of miR-491-3p were decreased in multidrug-resistant tongue cancer (TC) cells. Induction of miR-491-3p expression sensitized TC cells to chemotherapy. In agreement, functional inhibition of miR-491-3p enhanced resistance of TC cells to chemotherapy. We found that miR-491-3p directly targeted mTORC2 component Rictor and inhibited mTORC2 activity, which was increased in resistant TC cells with high p-Akt(Ser473), p-SGK1(Ser422) and p-FOXO1(Thr24) levels. Inhibition of mTORC2 activity via either Rictor knockdown or mTOR inhibitor in turn sensitized TC cells to chemotherapy. In agreement, overexpression of Rictor increased the mTORC2 activity and induced resistance of TC cells to chemotherapy. As a feedback loop, mTORC2 downregulated miR-491-3p expression by inactivating FOXO1, which otherwise would transcriptionally induce miR-491-3p expression. Levels of miR-491-3 and Rictor or mTORC2 activity negatively correlated in TC tissues. Finally, low levels of miR-491-3p and highly expressed Rictor were associated with poor prognosis in tongue cancer patients. These data provide a rationale for targeted intervention on miR-491-3p/mTORC2 axis to enhance the efficacy of chemotherapy against tongue cancer.

Ilm K, Kemmner W, Osterland M, et al.
High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients.
Mol Cancer. 2015; 14:38 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III.
FINDINGS: We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) by using the SPSS 2-step cluster function and Kaplan-Meier survival analysis.
CONCLUSION: According to our results, patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation. Moreover, we demonstrated that the "Traditional pathway" with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis. This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation.

Kessler T, Sahm F, Blaes J, et al.
Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.
Oncotarget. 2015; 6(31):31050-68 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

Soares HP, Ming M, Mellon M, et al.
Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2.
Mol Cancer Ther. 2015; 14(4):1014-23 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser(240/244)), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at Thr(37/46)), and mTORC2-mediated AKT phosphorylation at Ser(473), in a concentration-dependent manner. Strikingly, BEZ235 markedly enhanced the MEK/ERK pathway in a dose-dependent manner. Maximal ERK overactivation coincided with complete inhibition of phosphorylation of AKT and 4E-BP1. ERK overactivation was induced by other PI3K/TOR-KIs, including PKI-587 and GDC-0980. The MEK inhibitors U126 or PD0325901 prevented ERK overactivation induced by PI3K/TOR-KIs. The combination of BEZ235 and PD0325901 caused a more pronounced inhibition of cell growth than that produced by each inhibitor individually. Mechanistic studies assessing PI3K activity in single PDAC cells indicate that PI3K/TOR-KIs act through a PI3K-independent pathway. Doses of PI3K/TOR-KIs that enhanced MEK/ERK activation coincided with those that inhibited mTORC2-mediated AKT phosphorylation on Ser(473), suggesting a role of mTORC2. Knockdown of RICTOR via transfection of siRNA markedly attenuated the enhancing effect of BEZ235 on ERK phosphorylation. We propose that dual PI3K/mTOR inhibitors suppress a novel negative feedback loop mediated by mTORC2, thereby leading to enhanced MEK/ERK pathway activity in pancreatic cancer cells.

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